PINK1 Silencing Modifies Dendritic Spine Dynamics of Mouse Hippocampal Neurons

  • C. J. Hernández
  • C. Báez-Becerra
  • M. J. Contreras-Zárate
  • H. Arboleda
  • G. ArboledaEmail author


PTEN-induced kinase 1 (PINK1) mutations can cause early-onset Parkinson’s disease and patients are likely to develop cognitive decline, depression, and dementia. Several neurophysiological studies have demonstrated PINK1 deficiency impairs striatal and hippocampal presynaptic plasticity. Dendritic spine postsynaptic abnormalities are common in neurological diseases; however, whether PINK1 silencing modifies dendritic spine dynamics of hippocampal neurons is unclear. To address this question, confocal images of mouse cultured hippocampal neurons transfected with plasmids to silence PINK1 were analyzed. These studies revealed that PINK1 silencing increased density of thin spines and reduced head size of stubby spines. Immunoblotting analysis uncovered that PINK1 silencing decreased expression of postsynaptic density proteins (PSD95 and Shank) and glutamate receptors (NR2B and mGluR5). We also found PINK1 silencing regulated dendritic spine morphology by actin regulatory proteins (RhoGAP29 and ROCK2) and regulated neuronal survival by decreased Akt activation. These results suggest PINK1 may regulate postsynaptic plasticity in hippocampal neurons generating presymptomatic alterations in dendritic spines that eventually could lead to the neurodegeneration and cognitive decline often seen in Parkinson’s disease.


Parkinson’s disease PINK1 Dendritic spines Hippocampal neurons 


Funding Information

This work was supported by Research Division Bogotá-Universidad Nacional de Colombia (DIB-UNAL, Project No. 37405).

Compliance with Ethical Standards

All experiments were conducted in compliance with the National Institutes of Health Guidelines for Care and Use of Experimental Animals and approved by the Institutional Committee of Animal Care and Use at Universidad Nacional de Colombia-Bogotá.


  1. Ambrosi G, Cerri S, Blandini F (2014) A further update on the role of excitotoxicity in the pathogenesis of Parkinson’s disease. J Neural Transm 121(8):849–859. CrossRefGoogle Scholar
  2. Báez-Becerra C, Filipello F, Sandoval-Hernández A, Arboleda H, Arboleda G (2018) Liver X receptor agonist GW3965 regulates synaptic function upon amyloid beta exposure in hippocampal neurons. Neurotox Res 33(3):569–579. CrossRefGoogle Scholar
  3. Beaudoin GMJ, Lee S-H, Singh D, Yuan Y, Ng Y-G, Reichardt LF, Arikkath J (2012) Culturing pyramidal neurons from the early postnatal mouse hippocampus and cortex. Nat Protoc 7(9):1741–1754. CrossRefGoogle Scholar
  4. Brunet A, Datta SR, Greenberg ME (2001) Transcription-dependent and -independent control of neuronal survival by the PI3K-Akt signaling pathway. Curr Opin Neurobiol 11(3):297–305. CrossRefGoogle Scholar
  5. Chang N, Li L, Hu R, Shan Y, Liu B, Li L, Wang H, Feng H, Wang D, Cheung C, Liao M, Wan Q, (2010) Differential regulation of NMDA receptor function by DJ-1 and PINK1. Aging Cell 9 (5):837–850.
  6. Contreras-Zárate MJ, Niño A, Rojas L, Arboleda H, Arboleda G (2015) Silencing of PINK1 inhibits insulin-like growth factor-1-mediated receptor activation and neuronal survival. J Mol Neurosci 56(1):188–197. CrossRefGoogle Scholar
  7. Dagda RK, Pien I, Wang R, Zhu J, Wang KZQ, Callio J, Banerjee TD, Dagda RY, Chu CT (2014) Beyond the mitochondrion: cytosolic PINK1 remodels dendrites through protein kinase A. J Neurochem 128(6):864–877. CrossRefGoogle Scholar
  8. Davie CA (2008) A review of Parkinson’s disease. Br Med Bull 86(1):109–127. CrossRefGoogle Scholar
  9. Du F, Yu Q, Yan S, Hu G, Lue LF, Walker DG et al (2017) PINK1 signalling rescues amyloid pathology and mitochondrial dysfunction in Alzheimer’s disease. Brain 140(12):3233–3251. CrossRefGoogle Scholar
  10. Feligioni M, Mango D, Piccinin S, Imbriani P, Iannuzzi F, Caruso A, de Angelis F, Blandini F, Mercuri NB, Pisani A, Nisticò R (2016) Subtle alterations of excitatory transmission are linked to presynaptic changes in the hippocampus of PINK1-deficient mice. Synapse 70(6):223–230. CrossRefGoogle Scholar
  11. Fiala JC, Spacek J, Harris KM (2002) Dendritic spine pathology: cause or consequence of neurological disorders? Brain Res Rev 39:29–54. CrossRefGoogle Scholar
  12. Forrest MP, Parnell E, Penzes P (2018) Dendritic structural plasticity and neuropsychiatric disease. Nat Rev Neurosci 19:215–234. CrossRefGoogle Scholar
  13. Gautier CA, Kitada T, Shen J (2008) Loss of PINK1 causes mitochondrial functional defects and increased sensitivity to oxidative stress. Proc Natl Acad Sci 105(32):11364–11369. CrossRefGoogle Scholar
  14. George AJ, Gordon L, Beissbarth T, Koukoulas I, Holsinger RMD, Perreau V, Cappai R, Tan SS, Masters CL, Scott HS, Li QX (2010) A serial analysis of gene expression profile of the Alzheimer’s disease Tg2576 mouse model. Neurotox Res 17(4):360–379. CrossRefGoogle Scholar
  15. Guilmatre A, Huguet G, Delorme R, Bourgeron T (2014) The emerging role of SHANK genes in neuropsychiatric disorders. Developmental Neurobiology 74(2):113–122. CrossRefGoogle Scholar
  16. Hacohen-Kleiman G, Sragovich S, Karmon G, Gao A, Grigg I, Pasmanik-Chor M, Le A, Korenková V, McKinney R, Gozes I (2018) Activity-dependent neuroprotective protein deficiency models synaptic and developmental phenotypes of autism-like syndrome. J Clin Invest 128(11):4956–4969. CrossRefGoogle Scholar
  17. Kitada T, Pisani A, Porter D, Yamaguchi H, Tscherter A, Martella G, Bonsi P, Zhang C, Pothos E, Shen J (2007) Impaired dopamine release and synaptic plasticity in the striatum of PINK1-deficient mice. Proc Natl Acad Sci U S 104:11441–11446 CrossRefGoogle Scholar
  18. Madeo G, Schirinzi T, Martella G, Latagliata EC, Puglisi F, Shen J, Valente EM, Federici M, Mercuri NB, Puglisi-Allegra S, Bonsi P, Pisani A (2014) PINK1 heterozygous mutations induce subtle alterations in dopamine-dependent synaptic plasticity. Mov Disord 29(1):41–53. CrossRefGoogle Scholar
  19. Manczak M, Kandimalla R, Yin X, Reddy PH (2018) Hippocampal mutant APP and amyloid beta-induced cognitive decline, dendritic spine loss, defective autophagy, mitophagy and mitochondrial abnormalities in a mouse model of Alzheimer’s disease. Human Molecular Genetics 27(8, 15):1332–1342. CrossRefGoogle Scholar
  20. Meissner WG, Frasier M, Gasser T, Goetz CG, Lozano A, Piccini P, Obeso JA, Rascol O, Schapira A, Voon V, Weiner DM, Tison F, Bezard E (2011) Priorities in Parkinson’s disease research. Nat Rev Drug Discov 10(5):377–393. CrossRefGoogle Scholar
  21. Mills RD, Sim CH, Mok SS, Mulhern TD, Culvenor JG, Cheng HC (2008, April) Biochemical aspects of the neuroprotective mechanism of PTEN-induced kinase-1 (PINK1). J Neurochem 105:18–33. CrossRefGoogle Scholar
  22. Pearlstein E, Michel FJ, Save L, Ferrari DC, Hammond C (2016) Abnormal development of glutamatergic synapses afferent to dopaminergic neurons of the Pink1−/− mouse model of Parkinson’s disease. Front Cell Neurosci 10(168).
  23. Peters A, Kaiserman-Abramof IR (1970) The small pyramidal neuron of the rat cerebral cortex. The perikaryon, dendrites and spines. Am J Anat 127:321–355. CrossRefGoogle Scholar
  24. Qiao H, An S, Xu C, Ma X (2017) Role of proBDNF and BDNF in dendritic spine plasticity and depressive-like behaviors induced by an animal model of depression. Brain Res 1663:29–37. CrossRefGoogle Scholar
  25. Reddy PH, Yin XL, Manczak M, Kumar S, Pradeepkiran JA, Vijayan M, Reddy AP (2018) Mutant APP and amyloid beta-induced defective autophagy, mitophagy, mitochondrial structural and functional changes and synaptic damage in hippocampal neurons from Alzheimer’s disease. Hum Mol Genet 27(14):2502–2516. CrossRefGoogle Scholar
  26. Reetz K, Lencer R, Steinlechner S, Gaser C, Hagenah J, Büchel C, Petersen D, Kock N, Djarmati A, Siebner HR, Klein C, Binkofski F (2008) Limbic and frontal cortical degeneration is associated with psychiatric symptoms in PINK1 mutation carriers. Biol Psychiatry 64(3):241–247. CrossRefGoogle Scholar
  27. Rodriguez A, Ehlenberger DB, Dickstein DL, Hof PR, Wearne SL (2008) Automated three-dimensional detection and shape classification of dendritic spines from fluorescence microscopy images. PLoS One 3(4):e1997. CrossRefGoogle Scholar
  28. Shan Y, Liu B, Li L, Chang N, Li L, Wang H, Wang D, Feng H, Cheung C, Liao M, Cui T, Sugita S, Wan Q (2009) Regulation of PINK1 by NR2B-containing NMDA receptors in ischemic neuronal injury. J Neurochem 111(5):1149–1160. CrossRefGoogle Scholar
  29. Stankiewicz TR, Linseman DA (2014) Rho family GTPases: key players in neuronal development, neuronal survival, and neurodegeneration. Front Cell Neurosci 8.
  30. Truebestein L, Elsner DJ, Fuchs E, Leonard TA (2015) A molecular ruler regulates cytoskeletal remodelling by the Rho kinases. Nat Commun 6.
  31. Tu JC, Xiao B, Naisbitt S, Yuan JP, Petralia RS, Brakeman P, Doan A, Aakalu VK, Lanahan AA, Sheng M, Worley PF (1999) Coupling of mGluR/Homer and PSD-95 complexes by the Shank family of postsynaptic density proteins. Neuron 23:583–592. CrossRefGoogle Scholar
  32. Turrigiano GG (1999) Homeostatic plasticity in neuronal networks: the more things change, the more they stay the same. Trends Neurosci 22:221–227. CrossRefGoogle Scholar
  33. Valente EM, Abou-Sleiman PM, Caputo V, Muqit MMK, Harvey K, Gispert S et al (2004) Hereditary early-onset Parkinson’s disease caused by mutations in PINK1. Science 304(5674):1158–1160. CrossRefGoogle Scholar
  34. Venkatesh NM (1998) Synaptic plasticity: step-wise strengthening. Curr Biol 8(18):R650–R653. CrossRefGoogle Scholar
  35. Yu W, Sun Y, Guo S, Lu B (2011) The PINK1/Parkin pathway regulates mitochondrial dynamics and function in mammalian hippocampal and dopaminergic neurons. Hum Mol Genet 20(16):3227–3240. CrossRefGoogle Scholar
  36. Zhou H, Huang C, Tong J, Xia XG (2011) Early exposure to paraquat sensitizes dopaminergic neurons to subsequent silencing of PINK1 gene expression in mice. Int J Biol Sci 7(8):1180–1187. CrossRefGoogle Scholar

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Authors and Affiliations

  1. 1.Departamento de Patología, Facultad de Medicina e Instituto de GenéticaUniversidad Nacional de ColombiaBogotá DCColombia

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