The Role of Ceramide and Sphingosine-1-Phosphate in Alzheimer’s Disease and Other Neurodegenerative Disorders
Bioactive sphingolipids—ceramide, sphingosine, and their respective 1-phosphates (C1P and S1P)—are signaling molecules serving as intracellular second messengers. Moreover, S1P acts through G protein-coupled receptors in the plasma membrane. Accumulating evidence points to sphingolipids' engagement in brain aging and in neurodegenerative disorders such as Alzheimer’s, Parkinson’s, and Huntington’s diseases and amyotrophic lateral sclerosis. Metabolic alterations observed in the course of neurodegeneration favor ceramide-dependent pro-apoptotic signaling, while the levels of the neuroprotective S1P are reduced. These trends are observed early in the diseases’ development, suggesting causal relationship. Mechanistic evidence has shown links between altered ceramide/S1P rheostat and the production, secretion, and aggregation of amyloid β/α-synuclein as well as signaling pathways of critical importance for the pathomechanism of protein conformation diseases. Sphingolipids influence multiple aspects of Akt/protein kinase B signaling, a pathway that regulates metabolism, stress response, and Bcl-2 family proteins. The cross-talk between sphingolipids and transcription factors including NF-κB, FOXOs, and AP-1 may be also important for immune regulation and cell survival/death. Sphingolipids regulate exosomes and other secretion mechanisms that can contribute to either the spread of neurotoxic proteins between brain cells, or their clearance. Recent discoveries also suggest the importance of intracellular and exosomal pools of small regulatory RNAs in the creation of disturbed signaling environment in the diseased brain. The identified interactions of bioactive sphingolipids urge for their evaluation as potential therapeutic targets. Moreover, the early disturbances in sphingolipid metabolism may deliver easily accessible biomarkers of neurodegenerative disorders.
KeywordsAlzheimer’s disease Ceramide Huntington’s disease microRNA Parkinson’s disease Sphingosine-1-phosphate
Aging, which itself influences the central nervous system (CNS) in a relatively subtle manner, creates vulnerable background for the development of devastating disorders. Two of the most widespread neurodegenerative diseases are Alzheimer’s (AD) and Parkinson’s (PD). Dementia affects estimated 47 million people worldwide , placing enormous burden on the affected individuals, their families, societies, and healthcare systems. AD is the most common neurodegenerative disorder, responsible for up to 70% of dementia cases . This disease is characterized by the presence of aggregates of pathologically misfolded proteins, including the extracellular senile plaques built mainly of amyloid β (Aβ), a product of proteolytic cleavage of the transmembrane Aβ precursor protein (AβPP) by β- and γ-secretase . Neurons in AD also display cytoskeletal abnormalities that are linked to hyperphosphorylation and aggregation of the microtubule-associated tau protein into intracellular neurofibrillary tangles .
Parkinson’s disease is the most frequently occurring movement disease and the second most widespread neurodegenerative disorder after AD . It is estimated that PD affects up to 1% of people over the age of 60 and up to ca. 4% over 85 . PD is characterized by subcortical neurodegeneration, including the characteristic loss of dopaminergic phenotype neurons in substantia nigra pars compacta, loss of dopaminergic striatum innervation, and histopathological aberrations in the form of α-synuclein (ASN)-containing intracellular Lewy bodies (LB)/Lewy neurites (LN) . Disturbances in other neurotransmitter systems (serotoninergic, noradrenergic, and cholinergic) are increasingly being recognized along non-motor symptoms, which—in later stages—may include dementia . Like AD, Parkinsonian neurodegeneration progresses in a stealthy manner, and when clear symptoms appear the dopaminergic neuron population is already decimated .
Bioactive Sphingolipids Biosynthesis
Once merely considered structural compounds, bioactive sphingolipids are increasingly implicated as signaling molecules in the brain, and play important roles in aging, neurodegenerative disorders, and the accompanying immune deregulation . Ceramide, ceramide-1-phosphate (C1P), sphingosine, and sphingosine-1-phosphate (S1P) are the best described bioactive sphingolipids regulating stress resistance, proliferation, differentiation, and mature phenotypes of nervous system cells [8, 9]. Sphingolipids have multiple ancillary roles in the regulation of cell growth, death, senescence, adhesion, migration, inflammation, angiogenesis, and intracellular trafficking in the CNS [10, 11]. The sphingolipid rheostat model ascribed these compounds clearly opposite roles in cellular survival signaling: ceramide as a cell death activator, while C1P and S1P promoted survival. The fact that single phosphorylation reaction turns ceramide and sphingosine into their antagonistic counterparts stresses the significance of the precise, successful control of sphingolipid metabolism enzymes [8, 12]. Although the pro- versus anti-survival roles have blurred somewhat in recent years , the critical roles of sphingolipid signaling in nervous system function have been confirmed by effects of mutations in their biosynthesis and receptor genes [14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24]. The importance of bioactive sphingolipids is also stressed by the accumulating evidence about their involvement in aging and neurodegenerative disorders [8, 25, 26, 27, 28, 29].
The rate of ceramide biosynthesis is controlled by the first step of the pathway’s de novo branch, which is catalyzed by serine palmitoyltransferase (SPT). SPT product dihydrosphingosine is then metabolized by ceramide synthase (CERS) to dihydroceramide, which is subsequently converted by dihydroceramide desaturase (DES or DEGS) to ceramide. Ceramide may be metabolized into sphingomyelin by sphingomyelin synthase (SMS, or SGMS); the reverse reaction (the sphingomyelinase pathway) catalyzed by sphingomyelinases (SMases, SMPDs) is another major ceramide source. Ceramide also serves as a precursor for the production of sphingosine by ceramidases. CERS can perform the opposite reaction, which is third ceramide source, termed the salvage pathway. Sphingosine kinases (SPHK1, SPHK2) phosphorylate sphingosine into S1P in a highly regulated fashion in various cellular compartments; dephosphorylation is carried out by S1P phosphatases (SGPP1 and SGPP2), while S1P can be also hydrolyzed irreversibly into ethanolamine phosphate and hexadecenal by S1P lyase (SGPL) . Activity of the enzyme glucocerebrosidase (GBA) can be another ceramide source  with significant links to Parkinson’s disease (see Pt. 'The role of bioactive sphingolipids in Parkinson’s disease').
S1P and Ceramide in Neuronal Survival and Death Signaling
Ceramide controls not only multiple cell death mechanisms but also cellular senescence, differentiation, and aspects of arborization in neurons [37, 38]. Sphingosine also seems to be engaged in cell death modulation . C1P has been shown to stimulate cellular survival, growth, and may counteract ceramide signaling also through downregulation of acid sphingomyelinase and serine palmitoyltransferase activities [40, 41]. S1P regulates cell viability, neuronal excitability, and arborization . Sphingolipids are also engaged in immune phenomena, which critically alter the fate of brain cells in neurodegenerative disorders [31, 37, 38, 42, 43].
S1P can activate p38, ERK, and block Jnk in various tissues by acting through its surface G protein-coupled receptors  (however, S1P influence on Jnk can be more varied ) (Fig. 3b). ERK appears to mediate the pro-survival action of S1P . S1PRs also stimulate the anti-apoptotic PI3K-Akt pathway , whose disruption in AD may heavily contribute to the disease pathomechanism [71, 72]. The nuclear transcription factors targeted by S1P-sensitive pathways include FOXO3a (inhibited by the PI3K-Akt pathway ), AP-1 (a transcription factor receiving input from Jnk/p38/ERK [37, 73] and engaged in the network of mutual co-regulation between sphingolipid-related genes [48, 49, 50]), or NF-κB (nuclear factor κB, through direct interaction between SPHK1 with TNF receptor-associated factor TRAF2, and through S1P acting as TRAF2 cofactor [74, 75]). Moreover, histone deacetylases (HDAC1 and -2) are inhibited through S1P binding  and can block NF-κB via its deacetylation . NF-κB influence on cell death may vary depending on the signaling context, immune activation, etc.
Through PI3K-Akt, S1PRs can inhibit GSK-3β (the crucial tau kinase ) and the pro-apoptotic protein Bad. In addition, S1P has been shown to inhibit ceramide production by acid sphingomyelinase (aSMase) . However, contrary to the initial view on the clear-cut S1P-vs.-ceramide opposition, in some situations, S1P may actually exert neurotoxic influence—depending on the spatiotemporal control of its production and degradation, or when its concentration reaches too high levels . Moreover, it is necessary to bear in mind the mentioned ambiguous nature of some of S1P’s mediators: AP-1 , ERK [80, 81], or NF-κB [82, 83].
The roles of ceramides in cellular homoeostasis reach far beyond just being pro-apoptotic molecules. Loss of physiological ceramide concentrations can lead to structural disturbances in mitochondria and reduced respiration . Ceramides also regulate membrane dynamics, thus influencing other aspects of organellar function and life cycle such as mitochondrial fusion and fission, or vesicular transport . It is also well understood that their (patho)physiological roles are highly dependent on their chain length/CERS isoforms [86, 87]. When signaling apoptosis, ceramides appear to use a spectrum of mediators largely shared with S1P, albeit often in a contrasting way (Fig. 3a). Ceramides lead to dephosphorylation and inactivation of Akt via the protein phosphatase PP2A; this relieves Akt’s inhibitory influence on Bad and GSK-3β . On the other hand, ceramide-associated increase in reactive oxygen species (ROS) leads to the activation of p38 and Jnk and to ERK inhibition . The combined influence of p38, Jnk, and ERK modifies the activities of p53 and AP-1 (c-Fos, c-Jun) transcription factors . Together with Bad and GSK-3β activation, these changes cause mitochondrial alterations and via cytochrome c release and the activities of caspase-2, -3, -5, -8, and -9 may lead to axonal degeneration or neuron death . Ceramides might also directly form pores in the outer mitochondrial membrane, leading to the release of cytochrome c and other proteins . Other mitochondrial mediators of apoptosis known to be released in neurons by ceramides include apoptosis-inducing factor (AIF), the second mitochondrion-derived activator of caspase (Smac), and the stress-regulated endoprotease Omi . Ceramide-induced apoptosis thus involves both caspase-mediated and caspase-independent pathways.
As discussed above, changes in the balance between S1P and ceramide (Figs. 2 and 3) may not only influence apoptosis but also change the regulation of autophagy by the complex interplay between mTOR, beclin, and Bcl-2. S1P-dependent autophagy is thought to be a homeostatic, pro-survival response involved in the clearance of intracellular debris (damaged proteins/dysfunctional organelles) . In AD, autophagy can play critical role in the defense against oxidatively damaged cellular components, and its disturbances may exacerbate Aβ and tau deposition [90, 91]. However, autophagy can also constitute a mode of cell death, where autophagolysosomal degradation of mitochondria is dependent on the interaction between ceramide and LC3-II (lipidated microtubule-associated protein 1 light chain 3β) present on lysosomes  (Fig. 3).
Bioactive Sphingolipids in Aging
Bioactive sphingolipids have been investigated in the course of aging and in association with extreme longevity [27, 92, 93]. Centenarians display altered fatty acid pattern in ceramides and glucosylceramides—higher levels of sphingolipid species possibly linked to stress resistance (low oxidation susceptibility due to unsaturated fatty acid content) , while increased concentration of sphingomyelins (ceramide precursors) has been observed during aging . Sphingolipids appear to have significant influence on the course of aging; research on lower organism models suggests links between ceramide synthesis and longevity [8, 25, 95, 96, 97]. Importantly, bioactive sphingolipids are capable of influencing the IIS (insulin/insulin-like signaling)–PI3K–Akt, a highly conserved, versatile modulator of metabolism, aging, and stress response (Fig. 3) [98, 99, 100, 101, 102]. IGF-I signaling in the brain has been identified to negatively influence organism longevity also in mammals [103, 104], although some controversies persist . Results obtained in humans appear to support IIS role in aging [106, 107]. IIS seems to redirect the vital resources away from long-term investment in favor of more current needs such as metabolic regulation and cellular survival. This leads somewhat surprisingly to the trophic influence of IIS in the brain [8, 108, 109, 110, 111]. PI3K-Akt signaling regulates SPHKs and S1PRs expression/activity and intracellular sphingolipid transport [112, 113, 114, 115]. In turn, S1P receptors can differentially modulate Akt activity [116, 117, 118]. Ceramide leads to inhibition of Akt-dependent pro-survival signaling [47, 119, 120], while C1P stimulates it [121, 122].
The links between sphingolipids and cellular stress are an extremely important aspect of their potential involvement in aging (Fig. 3) [8, 67]. SPHK1 might inhibit ROS and reduce sensitivity to DNA damage . S1P and ceramides are under positive influence of the stress sensor p53, and faulty ROS control leads to alterations in S1P/ceramide signaling [67, 124, 125, 126]. Even more than in aging, stress and inappropriate stress responses are central elements of the pathomechanism of neurodegenerative disorders.
Bioactive Sphingolipids in the Pathomechanism of Alzheimer’s Disease
The pathogenesis of AD is not yet fully elucidated, and the actual roles of many of the observed disturbances are not clear. Accumulating evidence points to the involvement of bioactive sphingolipids in AD starting from the earliest, prodromal stages .
Well-documented mechanisms that induce neuronal and synaptic degeneration in AD brain include the following: oxidative damage, altered redox signaling, mitochondrial dysfunction, glucose hypometabolism/other metabolic stresses, Ca2+ deregulation, and inflammatory response. Many of these pathways are triggered and propagated due to the actions of soluble oligomers of Aβ peptide on neurons and glia. The role of ceramide/S1P was analyzed in the context of these damage pathways as well as the process of amyloidogenesis.
The Interactions Between Ceramide/S1P and AβPP/Aβ Metabolism
Structural roles of sphingolipids in cellular membranes including lipid rafts constitute an important aspect of their engagement in AβPP/Aβ metabolism . Lipid rafts are cholesterol- and sphingolipid-enriched microdomains of the plasma membrane described as signaling platforms [129, 130]. Rafts are strongly associated with Aβ production, and both β- and γ-secretases are enriched in these structures [129, 131, 132]. Lipid rafts also seem to influence Aβ aggregation . In turn oligomeric Aβ42 associates with rafts ; Aβ can change membrane fluidity, which may exert a feedback influence on its own production .
Rafts are sensitive to fluctuations in sphingolipid levels, leading, e.g., to changed properties of membrane-associated enzymes or receptors. Sphingolipid/ceramide deficiency leads to increased secretion of sAβPPα, the product of non-amyloidogenic cleavage. However, it also leads to enhanced secretion of Aβ42 possibly through modulation of raft-associated proteins and changes in raft membrane properties resulting in altered α- vs. β-cleavage ratio . Exogenous addition of ceramide and elevated endogenous ceramide increased the level of Aβ. C6-ceramide, a cell-permeable ceramide analogue, increased the rate of Aβ biosynthesis by affecting β-cleavage of AβPP. Lipid raft ceramides stabilize BACE1 (β-site AβPP cleaving enzyme 1, a β-secretase) . Additionally, it was shown that synthetic ceramide analogues may also function as γ-secretase modulators that increase Aβ42 production . FTY720 in turn has been demonstrated to reduce hippocampal neuron damage and the resulting learning and memory deficits in a rat model induced by bilateral, stereotactic injection of pre-aggregated Aβ42 into the hippocampus . Some of the neuroprotective effect might be ascribed to mobilization of extrasynaptic, N-methyl-D-aspartate receptors to the synapse (a phenomenon reducing cellular sensitivity to Aβ-induced neurotoxic calcium influx) . Importantly, FTY720 and KRP203 (another SPHK2 substrate that can bind S1PR upon phosphorylation) have been shown to reduce neuronal Aβ generation . However, the relationship between S1P and AβPP metabolism is still obscure, as the compounds used may as well downregulate S1PR-dependent signaling; moreover, FTY720 increased Aβ42 in mice in addition to reduction in Aβ40 . Positive correlation between S1P production by SPHK2 and AβPP processing has been reported . S1P produced by SPHK2 may activate BACE1, thus leading to higher release of Aβ peptides. S1P was shown to specifically bind to full-length BACE1 and to increase its proteolytic activity. The production of Aβ peptides can be reduced in N2a neuroblastoma cells by pharmacological inhibition of sphingosine kinases, homozygous SPHK2 gene deletion, or overexpression of the S1P lyase gene and SGPP1 phosphatase . A shift in SPHK2 subcellular distribution from cytosol to the nucleus was observed to correlate with Aβ deposition in AD brains by Dominguez and collaborators . In turn, Aβ production correlates with low SPHK1 and high S1P lyase protein . Disturbances in S1P observed in AD may not only critically regulate caspase-mediated AβPP cleavage. S1P regulates lysosomal AβPP metabolism in a calcium-dependent manner . S1P is also a pro-secretory molecule, and the dependence of AβPP secretion on S1P signaling has direct potential significance in AD . The regulation of gene expression via S1PRs and through intracellular signaling can also lead to complex changes in cellular metabolism. AβPP modulates this process, as shown in FTY720-treated mice overexpressing mutant (V717I) AβPP. FTY720, which raises significant hopes as a repurposed neuroprotective drug in AD, increased the gene expression of sphingosine kinases (SPHKs), ceramide kinase (CERK), and the anti-apoptotic Bcl-2 in an age-dependent manner .
The accumulated oligomerized Aβ peptide in AD brain may also promote ceramide formation, as demonstrated both in cell culture [148, 153, 154, 155, 156] and animal models . Imbalance in mRNA expression of enzymes responsible for S1P to ceramide ratio, which potentially might decide of the brain cell fates, is observed from the earliest clinically recognizable AD stages (Fig. 4) . Sphingomyelin hydrolysis stimulated by Aβ appears to be the main source of ceramides in the pathology of Alzheimer’s disease [155, 159, 160], along with de novo synthesis (expression of the de novo enzymes increases gradually during AD progression ). Activation of SPT by Aβ peptides has been observed, resulting in neurotoxic increase of ceramide levels via de novo pathway [148, 161]. Aβ induces apoptosis by activating aSMase and nSMase, thereby contributing to the increase in ceramide levels. Senile plaques contain aSMase and nSMase proteins along with high levels of saturated ceramides [63, 162], and aSMase activity is upregulated in human AD brains (Fig. 4) . Examples of genes upregulated by AD also included ceramide synthases CERS1 and CERS2, S1P lyase SGPL1, or serine palmitoyltransferase catalytic subunit SPTLC2, while the acid ceramidase ASAH1, ceramide kinase CERK, or—less obviously—CERS6 were reduced [131, 149]. However, contrary to the abovementioned results, Couttas et al.  have found an early loss of CERS2 activity at Braak stage I/II (temporal cortex) to III/IV (frontal cortex, hippocampus). An interesting but underexplored link has been identified between the still obscure physiological AβPP role and sphingolipid metabolism, as AβPP intracellular domain is capable of reducing the expression of SPTLC2, potentially keeping the whole sphingolipid metabolism under negative control . Aβ also disturbs S1P signaling, potentially shifting the balance towards a much more pro-apoptotic state (Figs. 2 and 4) . Aβ can downregulate the genes for SPHKs and diminish the level of S1P as observed in wild-type and AβPP-overexpressing PC12 cells in culture . The study by Couttas et al.  showed reduced S1P levels with increasing Braak stage in tissue samples taken from the CA1 region of the hippocampus, or gray and white matter of the inferior temporal gyrus (Fig. 4). AD brains also display upregulated expression of S1P lyase SGPL1 and S1P-metabolizing phosphatases [65, 149]. The studies of Ceccom et al.  showed a decrease in immunoreactivity of SPHK1, S1P receptor 1, and an increase in S1P lyase in samples taken from the frontal and entorhinal cortices from human AD brains. However, the complex influence of SPHK2 signaling on cell fate and neurodegeneration is reflected by the study of Takasugi et al.  who reported upregulation of SPHK2 activity in AD brain cortex while other authors reported reduction of its activity and mRNA in the hippocampus [65, 147].
Importantly, SPHKs’ roles include engagement in the regulation of inflammation, a phenomenon already exploited in the therapy of relapsing remitting multiple sclerosis . The known engagement of sphingolipids in the modulation of NF-κB signaling by TNF-α  and other factors strongly suggests widespread opportunities in this field. Aβ specifically modulates the expression of some S1P cell surface receptors in monocytes . Sphingolipid modulators inhibit the accumulation of mononuclear phagocytes in response to Aβ, leading to proposals of their use as therapeutic agents . In turn, anti-ceramide immunity might also contribute to the disease progression .
An important hint about the significance of sphingolipids in AD is the association of apolipoprotein E (ApoE whose polymorphisms are strongly linked to AD risk ), with the receptor-mediated signaling of secreted S1P . Moreover, correlation has been observed between SPHK activities/S1P content and ApoE allele (2.5× higher S1P/sphingosine ratio in the hippocampus of ApoE2 vs. ApoE4 carriers) in AD . Sphingolipids might be useful, accessible AD biomarkers [170, 171, 172] and—potentially—therapeutic targets .
S1P/Ceramide and the Exosome-Mediated Spread of AD Pathology
Exosomes are sphingomyelin- and ceramide-enriched vesicles created inside the multivesicular endosomes (MVE) and then secreted when MVE membrane fuses with the plasmalemma. Exosomes are engaged in intercellular communication and carry microRNAs (miRNAs), messenger RNAs (mRNAs), and protein- and lipid-based signaling molecules. Vesicles released by Aβ-treated astrocytes contain the pro-apoptotic prostate apoptosis response 4 (PAR-4) protein and cause apoptosis in naive cultures . Rodent exosomes can contain Aβ, BACE1, and presenilins 1 and 2 . Amyloid plaques in the AD brain contain an exosome marker . These results have led to a hypothesis that exosomes might seed Aβ aggregation . However, at least under some circumstances exosomes can also inhibit Aβ oligomerization and promote its microglia-mediated clearance . These results might explain the observed association of exosomes with Aβ as a physiological, neuroprotective phenomenon , at least in the healthy tissue. It is also possible that exosomes of various origin (e.g., neuronal vs. astrocyte) might exert opposite influence or that the exosomal membranes might facilitate Aβ aggregation independently of protein-mediated exosomal functions (e.g., Aβ degradation by exosomal insulin-degrading enzyme or neprilysin)—reviewed in . Additionally, exosomes can serve as a vehicle for the extracellular secretion and cell-to-cell transport of ASN and tau protein, potentially further supporting the spread of aggregation pathology [180, 181]. S1P receptor signaling has been implicated in exosomal cargo sorting: activity of the S1PR-regulated Rho family GTPases was necessary for the process, and Gβγ inhibitor blocked it . Exosome secretion can be modulated by the activity of neutral sphingomyelinase 2 (nSMase2) and sphingomyelin synthase 2 (SMS2), suggesting unique roles for these enzymes in AD [178, 183], and additional significance for the disturbed ceramide levels observed in the course of the disease, as discussed above.
The Role of Bioactive Sphingolipids in Parkinson’s Disease
The selective, spatially progressing neurodegeneration observed in PD defies full explanation, although hypotheses have been created that probably successfully identify and describe important aspects of its mechanism . Pathological aggregation of ASN inside neuronal cells is widely associated with PD; ASN might also play some role in AD . ASN binds lipid rafts, and negatively regulates S1PR1 signaling there . Moreover, the relatively recently recognized phenomenon of ASN secretion suggests links with sphingolipid signaling, as the engagement of sphingolipids in neuronal secretory pathways is well documented [7, 146]. ASN may undergo regulated secretion in a number of partially characterized mechanisms [45, 185, 186, 187, 188, 189, 190], possibly leading to the peptide being functionally “addressed” for different destinations, allowing passage of ASN (also oligomeric) into various compartments of recipient cells . This may have high significance for the postulated spread of ASN-induced pathology along anatomical connections .
The PD-linked changes may exert influence not only on neuronal survival and phenotype, but also potentially on the central mechanisms of PD pathology. Sphingomyelin has been demonstrated to modify the expression levels of ASN . Degradation of overexpressed or otherwise pathologically altered ASN may be dependent on the sphingomyelinase . Pharmacological inhibition of SPHK1/-2 activities in cells treated with low concentrations of MPP+ leads to enhanced secretion of ASN, which may strengthen the significance of the new, still underestimated mechanism of Parkinsonian pathology . Outside the CNS, FTY720 also reduced ASN burden in the enteric nervous system, improving gut motility whose reduction is an early peripheral symptom in PD . Interestingly, pramipexole (a dopamine D2/D3 receptor agonist) reversed SPHK1 inhibition in the MPTP model , suggesting further interactions between sphingolipid and dopamine signaling.
Glucocerebrosidase (GBA) is a lysosomal enzyme that produces ceramide from glucocerebroside (glucosylceramide) . GBA deficiency/mutations are among top genetic contributors to the development of PD [196, 213, 214] and are statistically associated with Parkinson’s disease [215, 216], contributing to its early development, rapid progression, and presence of additional psychiatric symptoms [217, 218]. Interestingly, β-glucocerebrosidase activity is reduced in the cerebrospinal fluid (CSF) of PD patients even if they do not carry any GBA1 mutations . Variants in the GBA gene may be highly useful in the prediction of PD course . Accumulation of glucosyl compounds and cholesterol has attracted most attention as the pathomechanism in GBA mutations/deficiency , but changes in ceramide levels cannot be excluded as an important contributing factor [214, 222]. The enzyme is important in ASN degradation  and appears to protect against ASN aggregation . Additionally, PD patients not carrying the GBA mutation also display elevated glucosylceramides in their plasma . Small-molecule GBA chaperones have been suggested as a possible means of therapy in synucleinopathies .
Sphingolipids in Huntington’s Disease and Amyotrophic Lateral Sclerosis
In recent years, data has been accumulating on the engagement of sphingolipids in Huntington’s disease (HD) and amyotrophic lateral sclerosis (ALS). HD is a neurodegenerative brain disorder involving striatum and cortex and manifesting itself in motor and cognitive disturbances. It is caused by a dominant mutation, a triplet expansion in the huntingtin (HTT) gene. HD appears to disturb sphingolipid metabolism; increased SGPL1 protein has been observed in the cortex and striatum of advanced HD postmortem brains, accompanied by striatal reduction in SPHK1 . Most data, however, has been obtained from animal models. Results suggest, similarly to other neurodegenerative disorders, that imbalance in sphingolipid concentrations and enzyme expression levels occurs in early stages of the disease development [227, 228, 229, 230]. SPTLC1 and CERS1 were reduced in the brains of R6/2 mice , a HD model mice transgenic for the first exon of huntingtin harboring ca. 160 CAG repeats . The altered sphingolipid metabolism has also been noted in a variety of other cellular and animal HD models , although the changes seem to be less clearly weighted towards cell death than in, e.g., AD . However, the reduced S1P levels observed in R6/2 mice  appear to be a relevant potential therapeutic target, as FTY720 has been demonstrated to improve neuronal activity, reduce brain atrophy, improve motor function, and increase R6/2 animal survival . Moreover, S1PR agonists increased huntingtin phosphorylation and reduced its aggregation [232, 233]. FTY720 also increased the levels of brain-derived neurotrophic factor (BDNF) levels and mitigated the upregulation of NF-κB, iNOS, and TNF-α that would otherwise lead to the potentially neurotoxic activation of astrocytes; FTY720 thus preserved synaptic plasticity and memory in R6/1 mice (another model with lower number of glutamine repeats in the first huntingtin exon) . The S1PR5 stimulator A-971432 preserved blood-brain barrier integrity in R6/2 mice . These results have led to proposal of S1P-modulating therapy of HD .
ALS is a neurodegenerative disorder encompassing motor neuron degeneration, muscle wasting, and paralysis, characterized by severe deregulation of metabolism, including lipid metabolism . Ceramides and their glucosyl and lactosyl derivatives are increased in ALS patient spinal cords . SOD mutant mouse model of ALS displays disturbances in the expression of genes related to immune regulation, exosomal secretion, or lysosomes. Importantly, disturbed levels of ceramides and sphingosine were noted to correlate with disease severity along with the expression of SPHK1, or SGPP2 and sphingolipids—sphingosine and ceramides (d18:1/26:0) . Increased glucosyl ceramide synthase (GCS) expression might hamper normalization of oxidative metabolism and motor recovery . Also in this case, FTY720 improved neurological scores and survival in SOD mutant mice . It modified the mRNA expression of, e.g., iNOS (reduced by the treatment), ARG1 (increased), BDNF (increased), and interleukin genes (IL-1β reduced, IL-10 increased), despite administration starting in the symptomatic phase .
MicroRNA Signaling and Bioactive Sphingolipids in Neurodegenerative Disorders
miRNAs are increasingly viewed as central regulators of neuronal homoeostasis, and their causal roles in neurodegenerative disorders are rapidly gaining attention. Deregulation of miRNA-based gene expression control may be a novel disease mechanism, but also delivers potentially valuable biomarkers of its development [240, 241, 242]. Considerable research interest has been generated concerning the role of miRNAs in the neuropathology of bioactive sphingolipids in several progressive age-related human neuropathological diseases, and especially how specific miRNAs may contribute to the dynamic molecular-genetic processes involving aberrant ceramide/C1P/S1P metabolism in both AD and PD. In humans, miRNAs are a family of 18–22 nt single-stranded RNAs that posttranslationally interact with, and regulate, the expression of mature mRNAs. Single upregulated miRNA can target multiple mRNAs to reduce their expression, and multiple miRNAs can target a single mRNA [243, 244, 245]. Whenever progressive neurodegeneration is encountered in central nervous tissues undergoing pathological change, progressive neuronal atrophy and brain cell death the NF-κB-sensitive, pro-inflammatory and potentially pathogenic miRNA species such as miRNA-34a, miRNA-146a, miRNA-155, and several others have been shown to be abundant (and readily detectable by hybridization methodologies) in the cytoplasm of degenerating neurons, as well as in both the extracellular fluid (ECF) and CSF, which is contiguous with ECF. While these miRNAs are normally required for the homeostatic operation of brain cellular and membrane-signaling functions, their upregulation and persistence in deteriorating nervous tissues and the nature of their interaction with biological membranes is associated with, and indicative of, the propagation and spreading of neurodegenerative disease. These miRNAs may be a diagnostic tool for the cytoplasmic status of brain cells at risk for neurodegeneration [241, 242, 243].
Immune regulators such as NF-κB, interleukins 4 and 17a, interleukin-1 receptor-associated kinase-1 (IRAK-1), or complement factor-H (CFH)
Neuronal activity/synaptic plasticity/scaffold genes such as glutamate receptor genes NR2A, GluR1, synaptobrevin 2, and synaptotagmin 1
Genes coding for glycolysis and oxidative phosphorylation proteins such as succinate dehydrogenase complex C, ubiquinol-cytochrome c reductase binding protein and ubiquinol-cytochrome c reductase complex III subunit VII (UQCRB and UQCRQ, respectively), or phosphofructokinase-1
Amyloidogenesis-linked genes such as the membrane protein tetraspanin 12 (TSPAN12), or the master postsynaptic membrane-organizing ankyrin-cytoskeletal protein SHANK3
Put another way, specific pathology-linked miRNAs appear to regulate a large number of plasma membrane-resident and plasma membrane-organizing components whose character is defined by sphingolipid composition, turnover, and metabolism.
Many CNS-abundant miRNAs have, in addition, important regulatory functions in the expression of enzymes involved in the generation of ceramide, sphingosine, C1P, S1P, and/or their receptors, both in healthy brain aging and in neurological disease. For example, the pro-inflammatory and rapidly induced NF-κB-regulated miRNA-155 (encoded in humans at chr 21q21.3) has been shown to regulate biosynthesis of the S1PR1 which functions in the amelioration of pathogenic inflammation in systemic autoimmune disease [246, 247, 248, 251]. Interestingly, a five-member cluster of miRNAs encoded on human chromosome 21 that includes let-7c, miRNA-99a, miRNA-125b, miRNA-155, and miRNA-802 may help explain the complex phenotypic diversity of trisomy 21 (Down’s syndrome; DS) and the strong linkage between DS and the aberrant sphingolipid and ceramide metabolism associated with trisomy 21 (DS) neuropathology [252, 253, 254]. Interestingly, some of the most recent brain biolipid research describes the association between neurotoxins secreted by the human gastrointestinal (GI) tract microbiome and inflammatory neurodegeneration of nervous tissues, a complex pathogenic process that is certain to involve CNS sphingolipid composition, their organization, and interactive metabolism [255, 256].
As mentioned earlier, sphingolipids are key regulators of exosomal secretion. Their roles include exosome formation, encapsulation, and miRNA shuttling across the plasma membrane . Exosomes and other extracellular vesicles secreted into the extracellular space from both neuronal and glial cells are enriched with the sphingolipid ceramide, as well as other more complex glycosphingolipids such as gangliosides, and may also be enriched in various species of pathogenic or “communicating” miRNAs [177, 243, 244, 245]. Such exosomal vesicle-bound miRNAs: (a) should be reflective of the sphingolipid and miRNA composition of the brain cell cytoplasm from which they were originally derived; (b) may serve the role as a novel form of intercellular communication among brain cells; (c) may carry selective miRNA ‘cargos’ that regulate both bioactive sphingosine/S1P and ceramide/C1P metabolism as well as other miRNA-mRNA targets in adjacent cells; (d) have been implicated in the inter-neuronal “spreading” of pathogenic signals via “paracrine” and related secretory effects in the diseased and neuro-degenerating brain; (e) have considerable potential for being clinically useful as a predictor and non-invasive diagnostic marker for AD and/or PD; and (f) may provide a “molecular-genetic” signature for a defined group of miRNAs associated with a particular neurological disease [177, 243, 244, 245, 246, 247, 248].
Recently, data on the engagement of miRNA-based gene regulation in HD and ALS begun to accumulate. Postmortem HD cortex samples from Brodmann’s area 4 reveal disturbed miRNA expression (reduced miR-9, miR-9*, miR-29b, miR-124a, miR-132) that might stem from loss of huntingtin-transcription factor interaction in neuronal cells . Numerous deregulated circulating miRNAs have been found in HD cases and might reflect not only the ongoing neurodegeneration but also altered communication with the periphery . Links between altered miRNAs and perturbations in apoptotic and cell cycle signaling have been proposed as a possible mechanism of cell loss in HD . The R6/2 mouse HD model displays reduction in miRNA-34a-5p, a member of miRNA-34 family that is engaged in p53- and SIRT1-dependent modulation of cell cycle, senescence, and apoptosis . A series of mouse models with various numbers of CAG repeats in the huntingtin gene has shown a repeat number- and brain part-dependent alteration in miRNA transcriptome (including miRNAs engaged in neuronal development/survival ). Altered miRNA levels in blood plasma and CSF have been proposed as HD biomarkers [263, 264].
The engagement of microRNAs in the pathology not only of neurons but also muscles is relatively better characterized in ALS . A high-throughput next-generation sequencing project has identified reduction in the blood levels of 38 miRNAs in sporadic ALS patients, including let-7 and miR-26 families. The pattern of reductions was dependent on the disease phenotypic expression and progression rate, making them potentially useful for diagnostic purposes . In turn, upregulation of miR-223-3p, miR-326, and miR-338-3p observed in tissue bank neuromuscular junction samples of ALS patients may disturb HIF-1 and brain-derived neurotrophic factor signaling . Disruption of the intraneuronal localization of RNAi machinery (leading to deregulated axonal protein synthesis) has also been noted as an important aspect of ALS pathology . Moreover, degenerating/dying neurons release miRNA-218 which leads to changes in astrocyte phenotype such as reduced expression of excitatory amino acid transporter 2 or peroxisome proliferator-activated receptor gamma coactivator 1α and to astrogliosis which likely contributes to the neuron loss .
Neurodegenerative disorders belong to the most widespread, devastating, and uncontrollable diseases. Alzheimer’s, Parkinson’s, and Huntington’s diseases and amyotrophic lateral sclerosis are, like physiological aging, increasingly associated with pronounced disturbances in the metabolism of bioactive sphingolipids (generally tending to augment the pro-apoptotic ceramide signaling at the expense of survival signals mediated by S1P). However, recent findings suggest a more complex picture, creating the need for refinement of current knowledge on of the roles of S1P and ceramides in the various cell death modes. The early appearance of sphingolipid alterations suggests their engagement in upstream steps of disease development. These observations raise hopes for identification of therapeutic targets that would allow reaching beyond the current symptomatic treatments. They also should help in the identification of highly usable biomarkers for the still elusive goal of early diagnosis.
Besides cell survival/death signaling, the roles of sphingolipids are more obscure. Their significance in the metabolism of AβPP/Aβ and ASN, with both proteins’ physiological roles still unclear, needs extensive insights before conclusions can be drawn. Similar is the significance of sphingolipids’ links with secretion mechanisms which can affect the spread of aggregating proteins, death/survival signals, or metabolic regulators such as noncoding RNAs. The significance of miRNAs for neurodegenerative disorders, although gaining increasing recognition in the field, is still largely uncharacterized.
A final question is that about the availability of therapeutic tools to manipulate the extremely complex network of sphingolipid metabolism. Some of the most basic needs may be met with currently available repurposed drugs such as fingolimod; however, it is highly possible that exploitation of sphingolipids as therapeutic targets (as opposed to their use in diagnosis) may require significant expansion of the current toolset.
The work was supported by the National Science Centre (PL) Grant No. 2013/11/N/NZ4/02233 (Chapters 1–4), an unrestricted grant to the LSU Eye Center from Research to Prevent Blindness (RPB) and a National Institute of Health (NIH) grant NIA AG038834 and Mossakowski Medical Research Centre Polish Academy of Sciences –T. No. 7 (Chapter 5).
Compliance with Ethical Standards
Conflict of Interest
The authors declare that they have no conflict of interest.
- 8.Jęśko H, Stępień A, Lukiw WJ, Strosznajder RP (2018) The cross-talk between sphingolipids and insulin-like growth factor signaling: significance for aging and neurodegeneration. Mol Neurobiol https://doi.org/10.1007/s12035-018-1286-3
- 11.Airola MV, Hannun YA (2013) Sphingolipid metabolism and neutral sphingomyelinases. In: Gulbins E., Petrache I. (eds) Sphingolipids: Basic Science and Drug Development. Handb Exp Pharmacol 215:57–76. Springer, Vienna. https://doi.org/10.1007/978-3-7091-1368-4_3
- 12.Motyl J, Strosznajder JB (2018) Sphingosine kinase 1/sphingosine-1-phosphate receptors dependent signalling in neurodegenerative diseases. The promising target for neuroprotection in Parkinson’s disease. Pharmacol Rep 70:1010–1014. https://doi.org/10.1016/j.pharep.2018.05.002 CrossRefPubMedGoogle Scholar
- 28.Couttas TA, Kain N, Suchowerska AK et al (2016) Loss of ceramide synthase 2 activity, necessary for myelin biosynthesis, precedes tau pathology in the cortical pathogenesis of Alzheimer’s disease. Neurobiol Aging 43:89–100. https://doi.org/10.1016/j.neurobiolaging.2016.03.027 CrossRefPubMedGoogle Scholar
- 33.Abdelbaset-Ismail A, Cymer M, Borkowska-Rzeszotek S, et al (2018) Bioactive phospholipids enhance migration and adhesion of human leukemic cells by inhibiting Heme oxygenase 1 (HO-1) and inducible nitric oxygenase synthase (iNOS) in a p38 MAPK-dependent manner. Stem Cell Rev https://doi.org/10.1007/s12015-018-9853-6
- 36.Rutherford C, Childs S, Ohotski J et al (2013) Regulation of cell survival by sphingosine-1-phosphate receptor S1P1 via reciprocal ERK-dependent suppression of Bim and PI-3-kinase/protein kinase C-mediated upregulation of Mcl-1. Cell Death Dis 4:e927. https://doi.org/10.1038/cddis.2013.455 CrossRefPubMedPubMedCentralGoogle Scholar
- 46.Motyl J, Przykaza Ł, Kosson P, Boguszewski P, Strosznajder J (2015) P.5.c.002 sphingosine kinase 1 mediated signalling in Parkinson’s disease animal model. Neuroprotective effect of fingolimod and a D2/D3 dopamine receptor agonist. Eur Neuropsychopharmacol 25:S586–S587. https://doi.org/10.1016/S0924-977X(15)30824-5 CrossRefGoogle Scholar
- 52.Dong Y-F, Guo R-B, Ji J et al (2018) S1PR3 is essential for phosphorylated fingolimod to protect astrocytes against oxygen-glucose deprivation-induced neuroinflammation via inhibiting TLR2/4-NFκB signalling. J Cell Mol Med 22:3159–3166. https://doi.org/10.1111/jcmm.13596 CrossRefPubMedPubMedCentralGoogle Scholar
- 64.Pchejetski D, Kunduzova O, Dayon A et al (2007) Oxidative stress-dependent sphingosine kinase-1 inhibition mediates monoamine oxidase A-associated cardiac cell apoptosis. Circ Res 100:41–49. https://doi.org/10.1161/01.RES.0000253900.66640.34 CrossRefPubMedGoogle Scholar
- 67.Van Brocklyn JR, Williams JB (2012) The control of the balance between ceramide and sphingosine-1-phosphate by sphingosine kinase: oxidative stress and the seesaw of cell survival and death. Comp Biochem Physiol B Biochem Mol Biol 163:26–36. https://doi.org/10.1016/j.cbpb.2012.05.006 CrossRefPubMedGoogle Scholar
- 71.Moloney AM, Griffin RJ, Timmons S et al (2010) Defects in IGF-1 receptor, insulin receptor and IRS-1/2 in Alzheimer’s disease indicate possible resistance to IGF-1 and insulin signalling. Neurobiol Aging 31:224–243. https://doi.org/10.1016/j.neurobiolaging.2008.04.002 CrossRefPubMedGoogle Scholar
- 76.Dai Y, Rahmani M, Dent P, Grant S (2005) Blockade of histone deacetylase inhibitor-induced RelA/p65 acetylation and NF-kappaB activation potentiates apoptosis in leukemia cells through a process mediated by oxidative damage, XIAP downregulation, and c-Jun N-terminal kinase 1 activation. Mol Cell Biol 25:5429–5444. https://doi.org/10.1128/MCB.25.13.5429-5444.2005 CrossRefPubMedPubMedCentralGoogle Scholar
- 77.Wang Y, Yang R, Gu J et al (2015) Cross talk between PI3K-AKT-GSK-3β and PP2A pathways determines tau hyperphosphorylation. Neurobiol Aging 36:188–200. https://doi.org/10.1016/j.neurobiolaging.2014.07.035 CrossRefPubMedGoogle Scholar
- 83.Kim A, Nam YJ, Lee CS (2017) Taxifolin reduces the cholesterol oxidation product-induced neuronal apoptosis by suppressing the Akt and NF-κB activation-mediated cell death. Brain Res Bull 134:63–71. https://doi.org/10.1016/j.brainresbull.2017.07.008 CrossRefPubMedGoogle Scholar
- 108.Ceda GP, Dall’Aglio E, Maggio M et al (2005) Clinical implications of the reduced activity of the GH-IGF-I axis in older men. J Endocrinol Investig 28:96–100Google Scholar
- 109.Okereke O, Kang JH, Ma J et al (2007) Plasma IGF-I levels and cognitive performance in older women. Neurobiol Aging 28:135–142. https://doi.org/10.1016/j.neurobiolaging.2005.10.012 CrossRefPubMedGoogle Scholar
- 114.Till KJ, Pettitt AR, Slupsky JR (2015) Expression of functional sphingosine-1 phosphate receptor-1 is reduced by B cell receptor signaling and increased by inhibition of PI3 kinase δ but not SYK or BTK in chronic lymphocytic leukemia cells. J Immunol 194:2439–2446. https://doi.org/10.4049/jimmunol.1402304 CrossRefPubMedPubMedCentralGoogle Scholar
- 115.Giussani P, Brioschi L, Bassi R et al (2009) Phosphatidylinositol 3-kinase/AKT pathway regulates the endoplasmic reticulum to golgi traffic of ceramide in glioma cells: a link between lipid signaling pathways involved in the control of cell survival. J Biol Chem 284:5088–5096. https://doi.org/10.1074/jbc.M808934200 CrossRefPubMedGoogle Scholar
- 116.Banno Y, Takuwa Y, Akao Y et al (2001) Involvement of phospholipase D in sphingosine 1-phosphate-induced activation of phosphatidylinositol 3-kinase and Akt in Chinese hamster ovary cells overexpressing EDG3. J Biol Chem 276:35622–35628. https://doi.org/10.1074/jbc.M105673200 CrossRefPubMedGoogle Scholar
- 120.Qin J, Berdyshev E, Poirer C et al (2012) Neutral sphingomyelinase 2 deficiency increases hyaluronan synthesis by up-regulation of Hyaluronan synthase 2 through decreased ceramide production and activation of Akt. J Biol Chem 287:13620–13632. https://doi.org/10.1074/jbc.M111.304857 CrossRefPubMedPubMedCentralGoogle Scholar
- 123.Huwiler A, Kotelevets N, Xin C et al (2011) Loss of sphingosine kinase-1 in carcinoma cells increases formation of reactive oxygen species and sensitivity to doxorubicin-induced DNA damage. Br J Pharmacol 162:532–543. https://doi.org/10.1111/j.1476-5381.2010.01053.x CrossRefPubMedPubMedCentralGoogle Scholar
- 144.Ceccom J, Loukh N, Lauwers-Cances V et al (2014) Reduced sphingosine kinase-1 and enhanced sphingosine 1-phosphate lyase expression demonstrate deregulated sphingosine 1-phosphate signaling in Alzheimer’s disease. Acta Neuropathol Commun 2:12. https://doi.org/10.1186/2051-5960-2-12 CrossRefPubMedPubMedCentralGoogle Scholar
- 147.Jęśko H, Wencel PL, Lukiw WJ, Strosznajder RP (2018) Modulatory effects of fingolimod (FTY720) on the expression of sphingolipid metabolism-related genes in an animal model of Alzheimer’s disease. Mol Neurobiol https://doi.org/10.1007/s12035-018-1040-x
- 149.Katsel P, Li C, Haroutunian V (2007) Gene expression alterations in the sphingolipid metabolism pathways during progression of dementia and Alzheimer’s disease: a shift toward ceramide accumulation at the earliest recognizable stages of Alzheimer’s disease? Neurochem Res 32:845–856. https://doi.org/10.1007/s11064-007-9297-x CrossRefPubMedGoogle Scholar
- 150.He X, Huang Y, Li B et al (2010) Deregulation of sphingolipid metabolism in Alzheimer’s disease. Neurobiol Aging 31:398–408. https://doi.org/10.1016/j.neurobiolaging.2008.05.010 CrossRefGoogle Scholar
- 151.Bandaru VVR, Troncoso J, Wheeler D et al (2009) ApoE4 disrupts sterol and sphingolipid metabolism in Alzheimer’s but not normal brain. Neurobiol Aging 30:591–599. https://doi.org/10.1016/j.neurobiolaging.2007.07.024 CrossRefPubMedGoogle Scholar
- 155.Ayasolla K, Khan M, Singh AK, Singh I (2004) Inflammatory mediator and beta-amyloid (25-35)-induced ceramide generation and iNOS expression are inhibited by vitamin E. Free Radic Biol Med 37:325–338. https://doi.org/10.1016/j.freeradbiomed.2004.04.007 CrossRefPubMedGoogle Scholar
- 161.Geekiyanage H, Upadhye A, Chan C (2013) Inhibition of serine palmitoyltransferase reduces Aβ and tau hyperphosphorylation in a murine model: a safe therapeutic strategy for Alzheimer’s disease. Neurobiol Aging 34:2037–2051. https://doi.org/10.1016/j.neurobiolaging.2013.02.001 CrossRefPubMedPubMedCentralGoogle Scholar
- 167.Dinkins MB, Dasgupta S, Wang G et al (2015) The 5XFAD mouse model of Alzheimer’s disease exhibits an age-dependent increase in anti-ceramide IgG and exogenous administration of ceramide further increases anti-ceramide titers and amyloid plaque burden. J Alzheimers Dis 46:55–61. https://doi.org/10.3233/JAD-150088 CrossRefPubMedPubMedCentralGoogle Scholar
- 171.Gizaw ST, Ohashi T, Tanaka M et al (2016) Glycoblotting method allows for rapid and efficient glycome profiling of human Alzheimer’s disease brain, serum and cerebrospinal fluid towards potential biomarker discovery. Biochim Biophys Acta 1860:1716–1727. https://doi.org/10.1016/j.bbagen.2016.03.009 CrossRefPubMedGoogle Scholar
- 174.Wang G, Dinkins M, He Q et al (2012) Astrocytes secrete exosomes enriched with proapoptotic ceramide and prostate apoptosis response 4 (PAR-4): potential mechanism of apoptosis induction in Alzheimer disease (AD). J Biol Chem 287:21384–21395. https://doi.org/10.1074/jbc.M112.340513 CrossRefPubMedPubMedCentralGoogle Scholar
- 179.Yuyama K, Igarashi Y (2017) Exosomes as carriers of Alzheimer’s amyloid-ß. Front Neurosci 11(229). https://doi.org/10.3389/fnins.2017.00229
- 183.Dinkins MB, Dasgupta S, Wang G et al (2014) Exosome reduction in vivo is associated with lower amyloid plaque load in the 5XFAD mouse model of Alzheimer’s disease. Neurobiol Aging 35:1792–1800. https://doi.org/10.1016/j.neurobiolaging.2014.02.012 CrossRefPubMedPubMedCentralGoogle Scholar
- 186.Christensen DP, Ejlerskov P, Rasmussen I, Vilhardt F (2016) Reciprocal signals between microglia and neurons regulate α-synuclein secretion by exophagy through a neuronal cJUN-N-terminal kinase-signaling axis. J Neuroinflammation 13:59. https://doi.org/10.1186/s12974-016-0519-5 CrossRefPubMedPubMedCentralGoogle Scholar
- 188.Ejlerskov P, Rasmussen I, Nielsen TT et al (2013) Tubulin polymerization-promoting protein (TPPP/p25α) promotes unconventional secretion of α-synuclein through exophagy by impairing autophagosome-lysosome fusion. J Biol Chem 288:17313–17335. https://doi.org/10.1074/jbc.M112.401174 CrossRefPubMedPubMedCentralGoogle Scholar
- 191.Zhang S, Eitan E, Wu T-Y, Mattson MP (2018) Intercellular transfer of pathogenic α-synuclein by extracellular vesicles is induced by the lipid peroxidation product 4-hydroxynonenal. Neurobiol Aging 61:52–65. https://doi.org/10.1016/j.neurobiolaging.2017.09.016 CrossRefPubMedGoogle Scholar
- 193.Sivasubramanian M, Kanagaraj N, Dheen ST, Tay SSW (2015) Sphingosine kinase 2 and sphingosine-1-phosphate promotes mitochondrial function in dopaminergic neurons of mouse model of Parkinson’s disease and in MPP+-treated MN9D cells in vitro. Neuroscience 290:636–648. https://doi.org/10.1016/j.neuroscience.2015.01.032 CrossRefPubMedGoogle Scholar
- 194.Motyl J, Przykaza Ł, Boguszewski PM, Kosson P, Strosznajder JB (2018) Pramipexole and Fingolimod exert neuroprotection in a mouse model of Parkinson's disease by activation of sphingosine kinase 1 and Akt kinase. Neuropharmacology 135:139–150. https://doi.org/10.1016/j.neuropharm.2018.02.023
- 198.Mielke MM, Maetzler W, Haughey NJ et al (2013) Plasma ceramide and glucosylceramide metabolism is altered in sporadic Parkinson’s disease and associated with cognitive impairment: a pilot study. PLoS One 8:e73094. https://doi.org/10.1371/journal.pone.0073094 CrossRefPubMedPubMedCentralGoogle Scholar
- 203.Foo J-N, Liany H, Bei J-X et al (2013) Rare lysosomal enzyme gene SMPD1 variant (p.R591C) associates with Parkinson’s disease. Neurobiol Aging 34:2890.e13–2890.e15. https://doi.org/10.1016/j.neurobiolaging.2013.06.010 CrossRefGoogle Scholar
- 209.Komnig D, Dagli CT, Habib P, et al (2018) Fingolimod (FTY720) is not protective in the subacute MPTP mouse model of Parkinson disease and does not lead to a sustainable increase of brain BDNF. J Neurochem https://doi.org/10.1111/jnc.14575
- 212.Vidal-Martínez G, Vargas-Medrano J, Gil-Tommee C et al (2016) FTY720/fingolimod reduces synucleinopathy and improves gut motility in A53T mice: contributions of pro-brain-derived neurotrophic factor (PRO-BDNF) and mature BDNF. J Biol Chem 291:20811–20821. https://doi.org/10.1074/jbc.M116.744029 CrossRefPubMedPubMedCentralGoogle Scholar
- 224.Abul Khair SB, Dhanushkodi NR, Ardah MT et al (2018) Silencing of glucocerebrosidase gene in Drosophila enhances the aggregation of Parkinson’s disease associated α-synuclein mutant A53T and affects locomotor activity. Front Neurosci 12:81. https://doi.org/10.3389/fnins.2018.00081 CrossRefPubMedPubMedCentralGoogle Scholar
- 225.Jung O, Patnaik S, Marugan J et al (2016) Progress and potential of non-inhibitory small molecule chaperones for the treatment of Gaucher disease and its implications for Parkinson disease. Expert Rev Proteomics 13:471–479. https://doi.org/10.1080/14789450.2016.1174583 CrossRefPubMedPubMedCentralGoogle Scholar
- 233.Di Pardo A, Castaldo S, Amico E et al (2018) Stimulation of S1PR5 with A-971432, a selective agonist, preserves blood-brain barrier integrity and exerts therapeutic effect in an animal model of Huntington’s disease. Hum Mol Genet 27:2490–2501. https://doi.org/10.1093/hmg/ddy153 CrossRefPubMedGoogle Scholar
- 234.Miguez A, García-Díaz Barriga G, Brito V, Straccia M, Giralt A, Ginés S, Canals JM, Alberch J (2015) Fingolimod (FTY720) enhances hippocampal synaptic plasticity and memory in Huntington’s disease by preventing p75NTR up-regulation and astrocyte-mediated inflammation. Hum Mol Genet 24(17):4958–4970. https://doi.org/10.1093/hmg/ddv218
- 238.Henriques A, Croixmarie V, Bouscary A, Mosbach A, Keime C, Boursier-Neyret C, Walter B, Spedding M et al (2018) Sphingolipid metabolism is dysregulated at transcriptomic and metabolic levels in the spinal cord of an animal model of amyotrophic lateral sclerosis. Front Mol Neurosci 10:433. https://doi.org/10.3389/fnmol.2017.00433
- 245.Sarkar S, Jun S, Rellick S et al (2016) Expression of microRNA-34a in Alzheimer’s disease brain targets genes linked to synaptic plasticity, energy metabolism, and resting state network activity. Brain Res 1646:139–151. https://doi.org/10.1016/j.brainres.2016.05.026 CrossRefPubMedPubMedCentralGoogle Scholar
- 249.Jaber V, Zhao Y, Lukiw WJ (2017) Alterations in micro RNA-messenger RNA (miRNA-mRNA) coupled signaling networks in sporadic Alzheimer’s disease (AD) hippocampal CA1. J Alzheimer’s Dis Park 7: https://doi.org/10.4172/2161-0460.1000312
- 251.MIR155 Gene—GeneCards | MIR155 RNA Gene. https://www.genecards.org/cgi-bin/carddisp.pl?gene=MIR155. Accessed 23 Jul 2018
- 253.Zhao Y, Jaber V, Percy ME, Lukiw WJ (2017) A microRNA cluster (let-7c, miRNA-99a, miRNA-125b, miRNA-155 and miRNA-802) encoded at chr21q21.1-chr21q21.3 and the phenotypic diversity of Down’s syndrome (DS; trisomy 21). J Nat Sci 3:Google Scholar
- 260.Das E, Jana NR, Bhattacharyya NP (2015) Delayed cell cycle progression in STHdh(Q111)/Hdh(Q111) cells, a cell model for Huntington’s disease mediated by microRNA-19a, microRNA-146a and microRNA-432. MicroRNA (Shariqah, United Arab Emirates) 4:86–100Google Scholar
Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.