Role of post-translational modifications in modulating the structure, function and toxicity of alpha-synuclein: implications for Parkinson's disease pathogenesis and therapies.
A better understanding of the molecular and cellular determinants that influence the pathology of Parkinson's disease (PD) is essential for developing effective diagnostic, preventative and therapeutic strategies to treat this devastating disease. A number of post-translational modifications to alpha-syn are present within the Lewy bodies in the brains of affected patients and transgenic models of PD and related disorders. However, whether disease-associated alpha-syn post-translational modifications promote or inhibit alpha-syn aggregation and neurotoxicity in vivo remains unknown. Herein, we summarize and discuss the major disease-associated post-translational modifications (phosphorylation, truncation and ubiquitination) and present our current understanding of the effect of these modifications on alpha-syn aggregation and toxicity. Elucidating the molecular mechanisms underlying post-translation modifications of alpha-syn and the consequences of such modifications on the biochemical, structural, aggregation and toxic properties of the protein is essential for unravelling the molecular basis of its function(s) in health and disease. Furthermore, the identification of the natural enzymes involved in regulating the post-translational modifications of alpha-synuclein will yield novel and more tractable therapeutic targets to treat PD and related synucleinopathies.
Oueslati
Abid
A
Laboratory of Molecular Neurobiology and Neuroproteomics, Brain Mind Institute, The Ecole Polytechnique Fédérale de Lausanne (EPFL), Lausanne, Switzerland.
Fournier
Margot
M
Lashuel
Hilal A
HA
D000818:Animals; D004195:Disease Models, Animal; D004330:Drosophila; D006801:Humans; D016631:Lewy Bodies / Q000235:genetics / Q000378:metabolism*; D010300:Parkinson Disease / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D010766:Phosphorylation; D011499:Protein Processing, Post-Translational; D051381:Rats; D054875:Ubiquitination; D051844:alpha-Synuclein / Q000235:genetics / Q000378:metabolism*
C497604:SNCA protein, human; D051844:alpha-Synuclein