Malfunctions in synaptic membrane trafficking in early pathology of Parkinson’s disease: new molecular clues

  • Elena Sopova Department of Neuroscience, Karolinska Institutet, 17177, Stockholm, Sweden; Institute of Translational Biomedicine, Saint Petersburg State University, Universitetskaya nab., 7–9, Saint Petersburg, 199034, Russian Federation
  • Olga Korenkova Institute of Translational Biomedicine, Saint Petersburg State University, Universitetskaya nab., 7–9, Saint Petersburg, 199034, Russian Federation
  • Oleg Shupliakov Department of Neuroscience, Karolinska Institutet, 17177, Stockholm, Sweden; Institute of Translational Biomedicine, Saint Petersburg State University, Universitetskaya nab., 7–9, Saint Petersburg, 199034, Russian Federation


The midbrain dopaminergic neurons of the substantia nigra and the ventral tegmental area play vital roles in the regulation of voluntary movement, emotion and reward in humans. These neurons are highly metabolic and are under constant oxidative stress. The dopaminergic neurons form extensive synaptic projections to the striatum. When these neurons start dying or when their synaptic connections fail, humans develop Parkinson's disease. This disease is accompanied by the accumulation of toxic α-synuclein-containing protein aggregates in nigrostriatal processes. Synucleins accumulate in a majority of healthy nerve terminals in the central nervous system, but what causes the formation of pathological synuclein aggregates is unclear. Recent studies point out that the interface between membrane trafficking in the nerve terminal and the autophagy–lysosomal pathway is the site for the aggregate assembly. An urgent goal is to find therapeutic targets at early stages of the disease when neurons are still functional.


synapse, synaptic proteins, atophagy-lysosomal pathway, developmental transcription factors, Parkinson's disease


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Bartels, T., Choi, J. G. and Selkoe, D. J. 2011. Alpha-synuclein occurs physiologically as a helically folded tetramer that resists aggregation. Nature 477(7362):107−110.

Boassa, D., Berlanga, M. L., Yang, M. A., Terada, M., Hu, J., Bushong, E. A., Hwang, M., Masliah, E., George, J. M. and Ellisman, M. H. 2013. Mapping the subcellular distribution of alpha-synuclein in neurons using genetically encoded probes for correlated light and electron microscopy: Implications for parkinson’s disease pathogenesis. Journal of Neuroscience 33(6):2605−2615.

Braak, H., Del Tredici, K., Rub, U., de Vos, R. A., Jansen Steur, E. N. and Braak, E. 2003. Staging of brain pathology related to sporadic parkinson’s disease. Neurobiology of Aging 24(2):197−211.

Burre, J., Sharma, M. and Sudhof, T. C. 2012. Systematic mutagenesis of alpha-synuclein reveals distinct sequence requirements for physiological and pathological activities. Journal of Neuroscience 32(43):15227−15242.

Burre, J., Vivona, S., Diao, J., Sharma, M., Brunger, A. T. and Sudhof, T. C. 2013. Properties of native brain alphasynuclein. Nature 498(7453):E4−E6; discussion E6-7.

Cao, M., Milosevic, I., Giovedi, S. and De Camilli, P. 2014. Upregulation of parkin in endophilin mutant mice. Journal of Neuroscience 34(49):16544−16549.

Cao, M., Wu, Y., Ashrafi, G., McCartney, A. J., Wheeler, H., Bushong, E. A., Boassa, D., Ellisman, M. H., Ryan, T. A. and De Camilli, P. 2017. Parkinson sac domain mutation in synaptojanin 1 impairs clathrin uncoating at synapses and triggers dystrophic changes in dopaminergic axons. Neuron 93(4):882−896 e885.

Chai, Y. J., Sierecki, E., Tomatis, V. M., Gormal, R. S., Giles, N., Morrow, I. C., Xia, D., Gotz, J., Parton, R. G., Collins, B. M., Gambin, Y. and Meunier, F. A. 2016. Munc18-1 is a molecular chaperone for alpha-synuclein, controlling its self-replicating aggregation. Journal of Cell Biology 214(6):705−718.

Chung, K. K., Zhang, Y., Lim, K. L., Tanaka, Y., Huang, H., Gao, J., Ross, C. A., Dawson, V. L. and Dawson, T. M. 2001. Parkin ubiquitinates the alpha-synuclein-interacting protein, synphilin-1: Implications for lewy-body formation in parkinson disease. Nature Medicine 7(10):1144−1150.

Cookson, M. R. and Bandmann, O. 2010. Parkinson’s disease: Insights from pathways. Human Molecular Genetics 19(R1):R21−R27.

Cuervo, A. M., Stefanis, L., Fredenburg, R., Lansbury, P. T. and Sulzer, D. 2004. Impaired degradation of mutant alphasynuclein by chaperone-mediated autophagy. Science 305(5688):1292−1295.

Engelender, S. 2008. Ubiquitination of alpha-synuclein and autophagy in parkinson’s disease. Autophagy 4(3):372−374.

Esposito, G., Ana Clara, F. and Verstreken, P. 2012. Synaptic vesicle trafficking and parkinson’s disease. Developmental Neurobiology 72(1):134−144.

Gad, H., Ringstad, N., Low, P., Kjaerulff, O., Gustafsson, J., Wenk, M., Di Paolo, G., Nemoto, Y., Crun, J., Ellisman, M. H., De Camilli, P., Shupliakov, O. and Brodin, L. 2000. Fission and uncoating of synaptic clathrin-coated vesicles are perturbed by disruption of interactions with the sh3 domain of endophilin. Neuron 27(2):301−312.

Guzman, J. N., Sanchez-Padilla, J., Wokosin, D., Kondapalli, J., Ilijic, E., Schumacker, P. T. and Surmeier, D. J. 2010. Oxidant stress evoked by pacemaking in dopaminergic neurons is attenuated by dj-1. Nature 468(7324):696−700.

Hansen, C. and Li, J. Y. 2012. Beyond alpha-synuclein transfer: Pathology propagation in parkinson’s disease. Trends in Molecular Medicine 18(5):248−255.

Heutink, P. and Verhage, M. 2012. Neurodegeneration: New road leads back to the synapse. Neuron 75(6):935−938.

Krabben, L., Fassio, A., Bhatia, V. K., Pechstein, A., Onofri, F., Fadda, M., Messa, M., Rao, Y., Shupliakov, O., Stamou, D., Benfenati, F. and Haucke, V. 2011. Synapsin i senses membrane curvature by an amphipathic lipid packing sensor motif. Journal of Neuroscience 31(49):18149−18154.

Laguna, A., Schintu, N., Nobre, A., Alvarsson, A., Volakakis, N., Jacobsen, J. K., Gomez-Galan, M., Sopova, E., Joodmardi, E., Yoshitake, T., Deng, Q., Kehr, J., Ericson, J., Svenningsson, P., Shupliakov, O. and Perlmann, T. 2015. Dopaminergic control of autophagic-lysosomal function implicates lmx1b in parkinson’s disease. Nature Neuroscience 18(6):826−835.

Lotharius, J. and Brundin, P. 2002. Pathogenesis of parkinson’s disease: Dopamine, vesicles and alpha-synuclein. Nature Reviews Neuroscience 3(12):932−942.

Luk, K. C., Kehm, V., Carroll, J., Zhang, B., O’Brien, P., Trojanowski, J. Q. and Lee, V. M. 2012. Pathological alpha-synuclein transmission initiates parkinson-like neurodegeneration in nontransgenic mice. Science 338(6109):949−953.

Mandler, M., Valera, E., Rockenstein, E., Weninger, H., Patrick, C., Adame, A., Santic, R., Meindl, S., Vigl, B., Smrzka, O., Schneeberger, A., Mattner, F. and Masliah, E. 2014. Nextgeneration active immunization approach for synucleinopathies: Implications for parkinson’s disease clinical trials. Acta Neuropathologica 127(6):861−879.

Maroteaux, L., Campanelli, J. T. and Scheller, R. H. 1988. Synuclein: A neuron-specific protein localized to the nucleus and presynaptic nerve terminal. Journal of Neuroscience 8(8):2804−2815.

Matta, S., Van Kolen, K., da Cunha, R., van den Bogaart, G., Mandemakers, W., Miskiewicz, K., De Bock, P. J., Morais, V. A., Vilain, S., Haddad, D., Delbroek, L., Swerts, J., Chavez-Gutierrez, L., Esposito, G., Daneels, G., Karran, E., Holt, M., Gevaert, K., Moechars, D. W., De Strooper, B. and Verstreken, P. 2012. Lrrk2 controls an endoa phosphorylation cycle in synaptic endocytosis. Neuron 75(6):1008−1021.

Milosevic, I., Giovedi, S., Lou, X., Raimondi, A., Collesi, C., Shen, H., Paradise, S., O’Toole, E., Ferguson, S., Cremona, O. and De Camilli, P. 2011. Recruitment of endophilin to clathrin-coated pit necks is required for efficient vesicle uncoating after fission. Neuron 72(4):587−601.

Moors, T. E., Hoozemans, J. J., Ingrassia, A., Beccari, T., Parnetti, L., Chartier-Harlin, M. C. and van de Berg, W. D. 2017. Therapeutic potential of autophagy-enhancing agents in parkinson’s disease. Molecular Neurodegeneration 12(1):11.

Murdoch, J. D., Rostosky, C. M., Gowrisankaran, S., Arora, A. S., Soukup, S. F., Vidal, R., Capece, V., Freytag, S., Fischer, A., Verstreken, P., Bonn, S., Raimundo, N. and Milosevic, I. 2016. Endophilin-a deficiency induces the foxo3afbxo32 network in the brain and causes dysregulation of autophagy and the ubiquitin-proteasome system. Cell Reports 17(4):1071−1086.

Olanow, C. W. and Brundin, P. 2013. Parkinson’s disease and alpha synuclein: Is Parkinson’s disease a prion-like disorder? Movement Disorders 28(1):31−40.

Papandreou, M. E. and Tavernarakis, N. 2017. Autophagy and the endo/exosomal pathways in health and disease. Biotechnology Journal 12(1).

Parkinson’s Disease, 2018. Retreived on April 18, 2018 from

Pechstein, A., Gerth, F., Milosevic, I., Japel, M., Eichhorn-Grunig, M., Vorontsova, O., Bacetic, J., Maritzen, T., Shupliakov, O., Freund, C. and Haucke, V. 2015. Vesicle uncoating regulated by sh3-sh3 domain-mediated complex formation between endophilin and intersectin at synapses. EMBO Reports 16(2):232−239.

Razdorskaya, V. V., Voskresenskaya, O. N., Yudina, G. K. 2016. Parkinson’s disease in Russia: prevalence and incidence. Saratov Journal of Medical Scientific Research 12(3):379−384.

Rivero-Rios, P., Madero-Perez, J., Fernandez, B. and Hilfiker, S. 2016. Targeting the autophagy/lysosomal degradation pathway in parkinson’s disease. Current Neuropharmacology 14(3):238−249.

Saheki, Y. and De Camilli, P. 2012. Synaptic vesicle endocytosis. Cold Spring Harbor Perspectives in Biology 4(9):a005645.

Schulz-Schaeffer, W. J. 2012. Neurodegeneration in parkinson disease: Moving lewy bodies out of focus. Neurology 79(24):2298−2299.

Scott, D. and Roy, S. 2012. Alpha-synuclein inhibits intersynaptic vesicle mobility and maintains recycling-pool homeostasis. Journal of Neuroscience 32(30):10129−10135.

Scott, D. A., Tabarean, I., Tang, Y., Cartier, A., Masliah, E. and Roy, S. 2010. A pathologic cascade leading to synaptic dysfunction in alpha-synuclein-induced neurodegeneration. Journal of Neuroscience 30(24):8083−8095.

Shehadeh, L., Mitsi, G., Adi, N., Bishopric, N. and Papapetropoulos, S. 2009. Expression of lewy body protein septin 4 in postmortem brain of parkinson’s disease and control subjects. Movement Disorders 24(2):204−210.

Soukup, S. F., Kuenen, S., Vanhauwaert, R., Manetsberger, J., Hernandez-Diaz, S., Swerts, J., Schoovaerts, N., Vilain, S., Gounko, N. V., Vints, K., Geens, A., De Strooper, B. and Verstreken, P. 2016. A lrrk2-dependent endophilina phosphoswitch is critical for macroautophagy at presynaptic terminals. Neuron 92(4):829−844.

Soukup, S. F. and Verstreken, P. 2017. Endoa/endophilin-a creates docking stations for autophagic proteins at synapses. Autophagy 13(5):971−972.

Staras, K., Branco, T., Burden, J. J., Pozo, K., Darcy, K., Marra, V., Ratnayaka, A. and Goda, Y. 2010. A vesicle superpool spans multiple presynaptic terminals in hippocampal neurons. Neuron 66(1):37−44.

Vargas, K. J., Makani, S., Davis, T., Westphal, C. H., Castillo, P. E. and Chandra, S. S. 2014. Synucleins regulate the kinetics of synaptic vesicle endocytosis. Journal of Neuroscience 34(28):9364−9376.

Wang, L., Das, U., Scott, D. A., Tang, Y., McLean, P. J. and Roy, S. 2014. Alpha-synuclein multimers cluster synaptic vesicles and attenuate recycling. Current Biology 24(19):2319−2326.

Woods, W. S., Boettcher, J. M., Zhou, D. H., Kloepper, K. D., Hartman, K. L., Ladror, D. T., Qi, Z., Rienstra, C. M. and George, J. M. 2007. Conformation-specific binding of alpha-synuclein to novel protein partners detected by phage display and nmr spectroscopy. Journal of Biological Chemistry 282(47):34555−34567.

Zhang, Y., Gao, J., Chung, K. K., Huang, H., Dawson, V. L. and Dawson, T. M. 2000. Parkin functions as an e2-dependent ubiquitin- protein ligase and promotes the degradation of the synaptic vesicle-associated protein, cdcrel-1. Proceedings of the National Academy of Science, USA 97(24):13354−13359.
How to Cite
Sopova, E., Korenkova, O., & Shupliakov, O. (2018). Malfunctions in synaptic membrane trafficking in early pathology of Parkinson’s disease: new molecular clues. Biological Communications, 62(4), 272–277.
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