Encyclopedia of Signaling Molecules

2018 Edition
| Editors: Sangdun Choi


Reference work entry
DOI: https://doi.org/10.1007/978-3-319-67199-4_101866


Historical Background

Synaptojanin 1 (SYNJ1) was discovered in 1994 as a brain-specific 145 kDa protein interacting with growth factor receptor-bound protein 2 (Grb2) and the phosphoprotein dynamin, involved in synaptic vesicle endocytosis and recycling (McPherson et al. 1994). SYNJ1 is a multidomain protein with a dual phosphoinositide phosphatase activity and is required for proper synaptic activity. Due to its high concentration in nerve terminals, its role in endocytosis has been widely studied and will be developed further in this article, but other unexpected roles are now emerging in different cell types and model organisms. In addition to its presynaptic functions, SYNJ1 is involved in internalization of AMPA receptors in postsynaptic compartments (Gong and Camilli 2008), in the regulation of T cell proliferation and cytokine responses after transplantation (Sun et al. 2013), and in the autophagosomal and endosomal trafficking (George et al. 2016).

SYNJ1 triplication is believed to be, at least in part, causative in Down’s syndrome associated with development of Alzheimer’s disease, whereas mutations in SYNJ1 were implicated in early-onset atypical Parkinsonism (Drouet and Lesage 2014), and, more recently, in intractable epilepsy with tau pathology (Dyment et al. 2015), and early-onset refractory seizures with progressive neurological decline (Hardies et al. 2016). The clinical spectrum associated with alterations of SYNJ1 will probably be expanded further in the near future thanks to the next-generation sequencing technologies.

SYNJ1 Gene and Protein

In 2000, human SYNJ1 was mapped to chromosome 21q22.11 (Cremona et al. 2000). This 99.29 kb-long gene is well conserved among species, from 27.6% of sequence similarity with the yeast orthologues INP51 and INP52 to 90% identity with mice SYNJ1 (Table 1).
SYNJ1, Table 1

SYNJ1 orthologues


Orthologue name

% identitya

Yeast (Saccharomyces cerevisiae)







Nematode (Caenorhabditis elegans)



Fruit fly (Drosophila melanogaster)



Lamprey (Petromyzon marinus)



Zebrafish (Danio rerio)



Rat (Rattus norvegicus)



Mouse (Mus musculus)



aPercentage of the orthologous sequence matching the human sequence

The human gene contains two open reading frames (ORFs) generating two main SYNJ1 isoforms of 170 and 145 kDa (isoform a, NP_003886.3, 1612 amino acids, and isoform b, NP_982271.2, 1350 amino acids). Two additional isoforms of unknown functional relevance are listed in RefSeq (isoform c, NP 001153774.1, 1295 amino acids, isoform d, NP 001153778.1, 1526 amino acids). SYNJ1 145 and 170 kDa isoforms are ubiquitously expressed, cytoplasmic, but the shorter isoform is highly expressed in the brain, localizing to presynaptic nerve terminals (McPherson et al. 1996; Ramjaun and McPherson 1996). Both isoforms contain a suppressor of actin1 (Sac1)-like domain at their N-terminal, a central 5-phosphatase domain, and a 250 amino acid C-terminal proline-rich domain (PRD). The longer 170 kDa isoform has an additional PRD (Fig. 1). SYNJ1 presents sequence identity with the Sac1 and 5-phosphatase domains of SYNJ2, the other main protein of the synaptojanin family, but harbors highly divergent C-terminal PRDs. These proteins may have overlapping functions in the central nervous system; however, SYNJ2 is expressed at lower levels. SYNJ1 and SYNJ2 belong to the inositol 5-phosphatases family, together with INPP5B (inositol polyphosphate-5-phosphatase B), INPP5D, INPP5E, INPP5J, INPP5K, INPPL1 (inositol polyphosphate phosphatase like 1), and OCRL (oculocerebrorenal syndrome of Lowe, inositol polyphosphate-5-phosphatase), but the configuration of tandem phosphatases is unique to synaptojanin (Billcliff and Lowe 2014).
SYNJ1, Fig. 1

Structure of the two major isoforms of SYNJ1. The 145 kDa (top) and the 170 kDa (bottom) SYNJ1 isoforms harbor two functional inositol phosphatase domains, an N-terminal Sac1 domain and a central 5-phosphatase domain. Several protein-protein interaction domains are found in the C-terminal part of the proteins: one or two PRD domains, AP2 binding motifs (WxxF, FxDxF, and DxF – in pink), and Eps15 binding motifs (NPF: asparagine-proline-phenylalanine – in blue). Two sites of phosphorylation, Ser1123 and Ser1202, are localized in the common PRD domain. Numbers indicate the amino acid positions along the proteins. Sac1 suppressor of actin1, PRD proline-rich domain, AP2 adaptor protein complex 2, Eps15 epidermal growth factor receptor pathway substrate 15 (modified from Drouet and Lesage 2014)

SYNJ1 Phosphatase Activity

To study physiological functions of SYNJ1, many models have been developed in various cell lines and organisms (mentioned in Table 1). Most of the studies focused on synapses, since SYNJ1 is highly enriched in presynaptic nerve terminals. Inactivation of SYNJ1 orthologues in mouse, nematode, lamprey, or yeast has revealed increased levels of phosphatidylinositol bisphosphates, an increased number of clathrin-coated vesicles, and a hypertrophy of the actin-rich matrix at endocytic zones. These works showed that SYNJ1 is essential for proper vesicle trafficking, uncoating of endocytic vesicles, actin cytoskeleton organization, and in early and late endosomes turnover; these functions are dependent on the ability of SYNJ1 to hydrolyze phosphoinositides (Cremona et al. 1999; Gad et al. 2000; Harris et al. 2000; Kim et al. 2002; Stefan et al. 2002).

Phosphoinositides, or phosphorylated inositol lipids, are essential components of eukaryotic membranes and important signaling molecules through the regulation of their phosphorylated state. The plasma membrane and endomembranes are enriched in distinct phosphoinositides which contribute to their identity as different subcellular compartments. Through this specific localization, phosphoinositides recruit specialized effector proteins to different cellular membranes. The inositol ring can be phosphorylated at three positions (D-3, D-4, or D-5), independently or simultaneously, by various phosphoinositide kinases. SYNJ1 is one of the 35 mammalian inositol phosphatases identified that can remove phosphate groups from phosphoinositides, but it is the major phosphatidylinositol trisphosphate (PI(3,4,5)P3) phosphatase in the brain. The Sac1 domain, homologous to the yeast SacIp, dephosphorylates predominantly phosphatidylinositol monophosphates present in organelles membranes, including those of the Golgi apparatus and endosomes, to recruit proteins needed for membrane trafficking. The 5-phosphatase domain hydrolyzes the phosphate group at the position D-5 of phosphatidylinositol bis- or trisphosphates, localized in plasma membrane, to activate endocytosis or cytoskeletal reorganization, among other pathways (Billcliff and Lowe 2014) (Fig. 2).
SYNJ1, Fig. 2

Phosphatase functions and interactors of SYNJ1. SYNJ1 Sac1 domain hydrolyzes phosphatidylinositol mono- and bisphosphate (PI(3)P, PI(4)P, and PI(3,5)P2) present at Golgi apparatus and endosome membranes, while the 5-phosphatase domain hydrolyzes phosphatidylinositol bis- and trisphosphate (PI(4,5)P2 and PI(3,4,5)P3) found on the plasma membrane to promote endocytosis and actin remodeling. The PRD domains and binding motifs allow interactions with partner proteins, depending on phosphorylation status, to target SYNJ1 to proper sites of phosphatase activity and to favor the assembly of the machinery for endocytosis

Study of zebrafish vision and vestibular mutants showed that SYNJ1 orthologue takes part in similar mechanisms in cone photoreceptors (George et al. 2014; Van Epps et al. 2004) and hair cells (Trapani et al. 2009). SYNJ1 is required for proper membrane trafficking and controls the number of vesicles released and timing of release at the synapses in sensory neurons. Endocytosis is also common in non-neuronal cells such as kidney podocytes, where the 170 kDa isoform of SYNJ1 promotes vesicle trafficking for an efficient glomerular filtration and thus for proper renal function (Soda et al. 2012).

SYNJ1 Interaction Network

SYNJ1 has to be properly targeted in space and time so that it can hydrolyze phosphoinositides where and when needed. Until recently, it was largely accepted that the cytoplasmic SYNJ1 protein was directed to endocytic sites thanks to protein-protein interactions through its C-terminal PRD domain with Src homology 3 (SH3) domain-containing proteins. Indeed, SYNJ1 PRD contains at least five potential SH3 domain-binding consensus sequences (Mayer and Eck 1995; McPherson et al. 1996). The 170 kDa isoform harbors an additional smaller PRD with at least three additional SH3 binding sites (Ramjaun and McPherson 1996) (Fig. 1). The C-terminal region common to both SYNJ1 isoforms was shown to interact with the SH3 domains of a variety of proteins implicated in synaptic vesicle recycling and trafficking, subcellular targeting, and signaling such as endophilin, amphiphysins, or intersectin (Cestra et al. 1999; de Heuvel et al. 1997; Micheva et al. 1997; Ringstad et al. 1997). The interaction motifs within SYNJ1 PRD are different for endophilin and amphiphysins (Cestra et al. 1999). However, recent work suggests that synaptojanin and endophilin interaction is PRD-SH3 independent (Dong et al. 2015). In this work done in C. elegans, the Sac1 domain plays an unexpected role in directly targeting SYNJ1 orthologue to synapses. Although the PRD-SH3 interactions do not seem to be required for SYNJ1 to function at endocytic sites, these may be required for other protein contacts in different subcellular compartments and may depend on the phosphorylated status of SYNJ1.

The 170 kDa splice variant bears an additional C-terminal tail that contains binding sites for clathrin, clathrin adaptor protein complex 2 (AP2), and the epidermal growth factor receptor pathway substrate 15 (Eps15) through asparagine-proline-phenylalanine (NPF) domain (Haffner et al. 1997; Krauß and Haucke 2007; Praefcke et al. 2004) (Fig. 1). The complex AP2 is a protein interaction hub binding all the endocytic components necessary for clathrin-mediated endocytosis (Praefcke et al. 2004). Its interaction with the long SYNJ1 isoform, via three types of binding motifs (WxxF, FxDxF, and DxF), is maintained through all the clathrin-endocytosis process, while the short isoform is only recruited at later stages to promote uncoating of vesicles immediately after fission (Perera et al. 2006).

SYNJ1 Phosphorylation Sites

SYNJ1 regulates the phosphorylated states of phosphoinositides but is also subjected to posttranslational modifications to adjust its activity in the cell (Fig. 1). It undergoes constitutive phosphorylation in unstimulated synapses and is dephosphorylated in a Ca2+-dependent manner upon stimulation by depolarization. SYNJ1 phosphatase activity and interaction with partner proteins are modified depending on the phosphorylation sites. In Drosophila, phosphorylation of SYNJ at S1029 (= S1123 in human, in the PRD domain, Fig. 1) by the Mnb kinase, enhances SYNJ phosphatase activity, decreases SYNJ-endophilin interactions, and is required for reliable synaptic vesicle recycling (Chen et al. 2014; Geng et al. 2016). In rats, phosphorylation of SYNJ1 at Ser1144 (= S1202 in human, in PRD domain, Fig. 1) by Cdk5 also inhibits SYNJ1 5-phosphatase activity (Lee et al. 2004). Cdk5 is responsible, at least in part, for the constitutive phosphorylation of SYNJ1.

SYNJ1 in Pathological Conditions

The critical importance of SYNJ1 at synapses led multiple teams to investigate its role in neurological disorders. Two types of alterations have linked SYNJ1 to neurological conditions: SYNJ1 triplication in Down’s syndrome (DS, or trisomy 21), associated with the early development of Alzheimer’s disease (AD), and SYNJ1 mutations in Parkinson’s disease (PD), intractable epilepsy with tau pathology, and early-onset refractory seizures with progressive neurological decline (Fig. 3).
SYNJ1, Fig. 3

Mutations found in SYNJ1 and associated pathologies. Two missense mutations were found in Sac1 domain and associated with early-onset atypical Parkinson’s disease. One stop mutation in the N-terminal part of the protein provokes intractable epilepsy and tau pathology. Four mutations, found in the 5-phosphatase or in the PRD domains, are linked to early-onset refractory seizures and neurological decline. The shorter 145 kDa isoform is represented because it is the most abundant in the brain

Even though there are many genes that are triplicated in DS, several lines of evidence strongly support a major role of SYNJ1 in this pathology: (i) SYNJ1 triplication triggers abnormal synaptic morphology in Drosophila neuromuscular junctions, (ii) early endosomes are enlarged in lymphoblastoid cell lines derived from DS patients, (iii) SYNJ1 overexpression in a DS mouse model is associated with higher phosphatase activity and learning deficits, and (iv) SYNJ1 protein levels in DS-affected brains show higher levels compared to matched controls. However, other genes triplicated in DS could be involved, alone or together with SYNJ1, to explain the deficits observed in DS patients. Many studies have also linked increased SYNJ1 levels with AD, showing a combined effect of SYNJ1 overexpression and Aβ oligomerization in the development of AD. Downregulation of SYNJ1 is now being investigated as a therapeutic strategy for AD, after SYNJ1 reduction was shown to be protective in a mouse model expressing the Swedish mutant of amyloid precursor protein and in an ApoE4 knock-in mouse model (McIntire et al. 2012; Zhu et al. 2015).

Since the first recurrent missense mutation Arg258Gln was identified in the Sac1 domain of SYNJ1 as the cause of recessive early-onset Parkinsonism, starting in the third decade of life with bradykinesia, dystonia, and variable atypical symptoms such as cognitive decline, seizures, and eyelid apraxia (Krebs et al. 2013; Olgiati et al. 2014; Quadri et al. 2013), another missense in the same domain, Arg459Pro, was identified in an Indian family (Kirola et al. 2016). The affected siblings presented tremor, bradykinesia, and rigidity, starting earlier than in the previously reported cases, with onset at 12 and 18 years old. Severe dystonia and dyskinesia were reported after treatment and were also observed in the six cases with Arg258Gln mutation, but no information was available on the presence of intellectual disability or seizures despite it was reported in some of the previous PD cases. Other mutations were recently reported but were associated to a different and more severe phenotype: early-onset treatment-resistant seizures and progressive neurological decline (Dyment et al. 2015; Hardies et al. 2016). In these works, four loss-of-function mutations p. Arg136*, p. Trp843*, pGln647Argfs*6, and p. Ser1122Thrfs*3 (at homozygous or compound heterozygous sates) were reported to reduce the levels of mutant transcript, while a fifth missense mutation p. Tyr8888Cys was located in the 5-phosphatase domain of SYNJ1 and was shown to affect both Sac1 and 5-phosphatase activity of SYNJ1 (Hardies et al. 2016). All the patients presented seizures at onset in the first days or months of life, with profound intellectual disability and a severe neurodegenerative course of the disease. Only one brain autopsy was performed and showed tau-immunoreactive neurofibrillary degeneration in the substantia nigra in the patient with the p. Arg136* mutation (Dyment et al. 2015). It will be of interest to investigate the presence of tau pathology in the two other cases to confirm whether the two studies report the same pathology and not two different phenotypes caused by a total loss of function of SYNJ1.

Altogether these data highlight that proper dosage and phosphatase activities of SYNJ1 are crucial for good brain functioning. Higher levels of SYNJ1 are correlated to DS associated with AD, while lower quantities, due to truncating mutations, provoke very severe seizures phenotype. The same epileptic phenotype is also observed when both phosphatase activities are reduced, meaning that hydrolysis of phosphoinositides is essential in synaptic transmission. Lastly, when only Sac1 function is altered, a more moderate and progressive pathology is observed (PD), suggesting a partial loss of function. Nevertheless, variable intellectual disability is observed in all these conditions, illustrating a central role of SYNJ1 in this aspect and controlling of lipid metabolism in the central nervous system as mandatory to preserve higher brain functions.


SYNJ1 is a phosphoinositide phosphatase protein, which is required for proper synaptic activity. The two phosphatase domains allow controlling the phosphoinositide balance in different subcellular compartments, but a new study also suggests that in addition to hydrolysis function, Sac1 is also required for proper targeting of the protein to the endocytosis sites. This finding in C. elegans model has however to be confirmed in other organisms. The regulation of lipid metabolism is highly dynamic at synapses, and therefore SYNJ1 activity is also tightly regulated by phosphorylation. There are probably more posttranslational modifications controlling SYNJ1 to be uncovered.

Altered levels of SYNJ1 expression and deficient phosphoinositide lipid hydrolysis are involved in several disorders. Appropriate levels of the protein are keys to maintain lipid balance in the cell, and disequilibrium in one direction or the other leads to neurological symptoms. Reduction of SYNJ1 activity is now being investigated as a therapeutic strategy to counteract AD. Even if promising results were obtained in mice models, the new discovery of severe epileptic syndromes associated with lower levels of SYNJ1 transcripts may limit some applications because proper balance will be hard to achieve and preserve over time in the progressive neurodegenerative pathology such as AD. Thanks to new sequencing technologies, we can anticipate that more mutations and copy variation numbers will be discovered. It will provide precious information to decipher the precise functions of SYNJ1 and help identify potential therapeutic targets for the SYNJ1-related affections.


  1. Billcliff PG, Lowe M. Inositol lipid phosphatases in membrane trafficking and human disease. Biochem J. 2014;461(2):159–75.PubMedCrossRefGoogle Scholar
  2. Cestra G, Castagnoli L, Dente L, Minenkova O, Petrelli A, Migone N, et al. The SH3 domains of endophilin and amphiphysin bind to the proline-rich region of synaptojanin 1 at distinct sites that display an unconventional binding specificity. J Biol Chem. 1999;274(45):32001–7.PubMedCrossRefGoogle Scholar
  3. Chen C-K, Bregere C, Paluch J, Lu J, Dickman DK, Chang KT. Activity-dependent facilitation of Synaptojanin and synaptic vesicle recycling by the Minibrain kinase. Nat Commun. 2014;5:4246.PubMedPubMedCentralGoogle Scholar
  4. Cremona O, Di Paolo G, Wenk MR, Lüthi A, Kim WT, Takei K, et al. Essential role of phosphoinositide metabolism in synaptic vesicle recycling. Cell. 1999;99(2):179–88.PubMedCrossRefGoogle Scholar
  5. Cremona O, Nimmakayalu M, Haffner C, Bray-Ward P, Ward DC, De Camilli P. Assignment of SYNJ1 to human chromosome 21q22.2 and Synj12 to the murine homologous region on chromosome 16C3-4 by in situ hybridization. Cytogenet Cell Genet. 2000;88(1–2):89–90.PubMedCrossRefGoogle Scholar
  6. Dong Y, Gou Y, Li Y, Liu Y, Bai J. Synaptojanin cooperates in vivo with endophilin through an unexpected mechanism. eLife. 2015; 4. Available from: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4435004/
  7. Drouet V, Lesage S. Synaptojanin 1 mutation in Parkinson’s disease brings further insight into the neuropathological mechanisms. Biomed Res Int. 2014;2014. Available from: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4181773/
  8. Dyment DA, Smith AC, Humphreys P, Schwartzentruber J, Beaulieu CL, Bulman DE, et al. Homozygous nonsense mutation in SYNJ1 associated with intractable epilepsy and tau pathology. Neurobiol Aging. 2015;36(2):1222.e1–5.CrossRefGoogle Scholar
  9. Gad H, Ringstad N, Löw P, Kjaerulff O, Gustafsson J, Wenk M, et al. Fission and uncoating of synaptic clathrin-coated vesicles are perturbed by disruption of interactions with the SH3 domain of endophilin. Neuron. 2000;27(2):301–12.PubMedCrossRefGoogle Scholar
  10. Geng J, Wang L, Lee JY, Chen C-K, Chang KT. Phosphorylation of synaptojanin differentially regulates endocytosis of functionally distinct synaptic vesicle pools. J Neurosci. 2016;36(34):8882–94.PubMedPubMedCentralCrossRefGoogle Scholar
  11. George AA, Hayden S, Holzhausen LC, Ma EY, Suzuki SC, Brockerhoff SE. Synaptojanin 1 is required for endolysosomal trafficking of synaptic proteins in cone photoreceptor inner segments. PLoS ONE. 2014;9(1):e84394.PubMedPubMedCentralCrossRefGoogle Scholar
  12. George AA, Hayden S, Stanton GR, Brockerhoff SE. Arf6 and the 5′phosphatase of Synaptojanin 1 regulate autophagy in cone photoreceptors. Cell. 2016;1(2):117–33.Google Scholar
  13. Gong L-W, Camilli PD. Regulation of postsynaptic AMPA responses by synaptojanin 1. Proc Natl Acad Sci. 2008;105(45):17561–6.PubMedPubMedCentralCrossRefGoogle Scholar
  14. Haffner C, Takei K, Chen H, Ringstad N, Hudson A, Butler MH, et al. Synaptojanin 1: localization on coated endocytic intermediates in nerve terminals and interaction of its 170 kDa isoform with Eps15. FEBS Lett. 1997;419(2–3):175–80.PubMedCrossRefGoogle Scholar
  15. Hardies K, Cai Y, Jardel C, Jansen AC, Cao M, May P, et al. Loss of SYNJ1 dual phosphatase activity leads to early onset refractory seizures and progressive neurological decline. Brain. 2016;139(9):2420–30.PubMedPubMedCentralCrossRefGoogle Scholar
  16. Harris TW, Hartwieg E, Horvitz HR, Jorgensen EM. Mutations in synaptojanin disrupt synaptic vesicle recycling. J Cell Biol. 2000;150(3):589–600.PubMedPubMedCentralCrossRefGoogle Scholar
  17. de Heuvel E, Bell AW, Ramjaun AR, Wong K, Sossin WS, McPherson PS. Identification of the major synaptojanin-binding proteins in brain. J Biol Chem. 1997;272(13):8710–6.PubMedCrossRefGoogle Scholar
  18. Kim WT, Chang S, Daniell L, Cremona O, Paolo GD, Camilli PD. Delayed reentry of recycling vesicles into the fusion-competent synaptic vesicle pool in synaptojanin 1 knockout mice. Proc Natl Acad Sci. 2002;99(26):17143–8.PubMedPubMedCentralCrossRefGoogle Scholar
  19. Kirola L, Behari M, Shishir C, Thelma BK. Identification of a novel homozygous mutation Arg459Pro in SYNJ1 gene of an Indian family with autosomal recessive juvenile Parkinsonism. Parkinsonism Relat Disord. 2016;31:124–8.PubMedCrossRefGoogle Scholar
  20. Krauß M, Haucke V. Phosphoinositide-metabolizing enzymes at the interface between membrane traffic and cell signalling. EMBO Rep. 2007;8(3):241–6.PubMedPubMedCentralCrossRefGoogle Scholar
  21. Krebs CE, Karkheiran S, Powell JC, Cao M, Makarov V, Darvish H, et al. The Sac1 domain of SYNJ1 identified mutated in a family with early-onset progressive Parkinsonism with generalized seizures. Hum Mutat. 2013;34(9):1200–7.PubMedPubMedCentralCrossRefGoogle Scholar
  22. Lee SY, Wenk MR, Kim Y, Nairn AC, De Camilli P. Regulation of synaptojanin 1 by cyclin-dependent kinase 5 at synapses. Proc Natl Acad Sci USA. 2004;101(2):546–51.PubMedPubMedCentralCrossRefGoogle Scholar
  23. Mayer BJ, Eck MJ. SH3 domains: minding your p’s and q’s. Curr Biol. 1995;5(4):364–7.PubMedCrossRefGoogle Scholar
  24. McIntire LBJ, Berman DE, Myaeng J, Staniszewski A, Arancio O, Di Paolo G, et al. Reduction of synaptojanin 1 ameliorates synaptic and behavioral impairments in a mouse model of Alzheimer’s disease. J Neurosci. 2012;32(44):15271–6.PubMedPubMedCentralCrossRefGoogle Scholar
  25. McPherson PS, Czernik AJ, Chilcote TJ, Onofri F, Benfenati F, Greengard P, et al. Interaction of Grb2 via its Src homology 3 domains with synaptic proteins including synapsin I. Proc Natl Acad Sci. 1994;91(14):6486–90.PubMedPubMedCentralCrossRefGoogle Scholar
  26. McPherson PS, Garcia EP, Slepnev VI, David C, Zhang X, Grabs D, et al. A presynaptic inositol-5-phosphatase. Nature. 1996;379(6563):353–7.PubMedCrossRefGoogle Scholar
  27. Micheva KD, Ramjaun AR, Kay BK, McPherson PS. SH3 domain-dependent interactions of endophilin with amphiphysin. FEBS Lett. 1997;414(2):308–12.PubMedCrossRefGoogle Scholar
  28. Olgiati S, De Rosa A, Quadri M, Criscuolo C, Breedveld GJ, Picillo M, et al. PARK20 caused by SYNJ1 homozygous Arg258Gln mutation in a new Italian family. Neurogenetics. 2014. doi: 10.1007/s10048-014-0406-0.Google Scholar
  29. Perera RM, Zoncu R, Lucast L, Camilli PD, Toomre D. Two synaptojanin 1 isoforms are recruited to clathrin-coated pits at different stages. Proc Natl Acad Sci. 2006;103(51):19332–7.PubMedPubMedCentralCrossRefGoogle Scholar
  30. Praefcke GJ, Ford MG, Schmid EM, Olesen LE, Gallop JL, Peak-Chew S-Y, et al. Evolving nature of the AP2 α-appendage hub during clathrin-coated vesicle endocytosis. EMBO J. 2004;23(22):4371–83.PubMedPubMedCentralCrossRefGoogle Scholar
  31. Quadri M, Fang M, Picillo M, Olgiati S, Breedveld GJ, Graafland J, et al. Mutation in the SYNJ1 gene associated with autosomal recessive, early-onset Parkinsonism. Hum Mutat. 2013;34(9):1208–15.PubMedCrossRefGoogle Scholar
  32. Ramjaun AR, McPherson PS. Tissue-specific alternative splicing generates two synaptojanin isoforms with differential membrane binding properties. J Biol Chem. 1996;271(40):24856–61.PubMedCrossRefGoogle Scholar
  33. Ringstad N, Nemoto Y, Camilli PD. The SH3p4/Sh3p8/SH3p13 protein family: binding partners for synaptojanin and dynamin via a Grb2-like Src homology 3 domain. Proc Natl Acad Sci. 1997;94(16):8569–74.PubMedPubMedCentralCrossRefGoogle Scholar
  34. Soda K, Balkin DM, Ferguson SM, Paradise S, Milosevic I, Giovedi S, et al. Role of dynamin, synaptojanin, and endophilin in podocyte foot processes. J Clin Invest. 2012;122(12):4401–11.PubMedPubMedCentralCrossRefGoogle Scholar
  35. Stefan CJ, Audhya A, Emr SD. The yeast synaptojanin-like proteins control the cellular distribution of phosphatidylinositol (4,5)-bisphosphate. Mol Biol Cell. 2002;13(2):542–57.PubMedPubMedCentralCrossRefGoogle Scholar
  36. Sun Y, Tawara I, Zhao M, Qin ZS, Toubai T, Mathewson N, et al. Allogeneic T cell responses are regulated by a specific miRNA-mRNA network. J Clin Invest. 2013;123(11):4739–54.PubMedPubMedCentralCrossRefGoogle Scholar
  37. Trapani JG, Obholzer N, Mo W, Brockerhoff SE, Nicolson T. Synaptojanin1 is required for temporal fidelity of synaptic transmission in hair cells. PLoS Genet. 2009;5(5):e1000480.PubMedPubMedCentralCrossRefGoogle Scholar
  38. Van Epps HA, Hayashi M, Lucast L, Stearns GW, Hurley JB, De Camilli P, et al. The zebrafish nrc mutant reveals a role for the polyphosphoinositide phosphatase synaptojanin 1 in cone photoreceptor ribbon anchoring. J Neurosci. 2004;24(40):8641–50.PubMedCrossRefGoogle Scholar
  39. Zhu L, Zhong M, Elder GA, Sano M, Holtzman DM, Gandy S, et al. Phospholipid dysregulation contributes to ApoE4-associated cognitive deficits in Alzheimer’s disease pathogenesis. Proc Natl Acad Sci USA. 2015;112(38):11965–70.PubMedPubMedCentralCrossRefGoogle Scholar

Copyright information

© Springer International Publishing AG 2018

Authors and Affiliations

  • Valérie Drouet
    • 1
    • 2
    • 3
    • 4
  • Suzanne Lesage
    • 1
    • 2
    • 3
    • 4
  • Alexis Brice
    • 1
    • 2
    • 3
    • 4
    • 5
  1. 1.UPMC Université Paris 6 UMR S 1127Sorbonne UniversitésParisFrance
  2. 2.Inserm U 1127, 75013ParisFrance
  3. 3.CNRS UMR 7225ParisFrance
  4. 4.Institut du Cerveau et de la Moelle épinière, ICMParisFrance
  5. 5.Department of Genetics and CytogeneticsAP-HP, Hôpital de la SalpêtrièreParisFrance