title: The contribution of alpha synuclein to neuronal survival and function - Implications for Parkinson's disease.
abstract: The aggregation of alpha synuclein (α-syn) is a neuropathological feature that defines a spectrum of disorders collectively termed synucleinopathies, and of these, Parkinson's disease (PD) is arguably the best characterized. Aggregated α-syn is the primary component of Lewy bodies, the defining pathological feature of PD, while mutations or multiplications in the α-syn gene result in familial PD. The high correlation between α-syn burden and PD has led to the hypothesis that α-syn aggregation produces toxicity through a gain-of-function mechanism. However, α-syn has been implicated to function in a diverse range of essential cellular processes such as the regulation of neurotransmission and response to cellular stress. As such, an alternative hypothesis with equal explanatory power is that the aggregation of α-syn results in toxicity because of a toxic loss of necessary α-syn function, following sequestration of functional forms α-syn into insoluble protein aggregates. Within this review, we will provide an overview of the literature linking α-syn to PD and the knowledge gained from current α-syn-based animal models of PD. We will then interpret these data from the viewpoint of the α-syn loss-of-function hypothesis and provide a potential mechanistic model by which loss of α-syn function could result in at least some of the neurodegeneration observed in PD. By providing an alternative perspective on the etiopathogenesis of PD and synucleinopathies, this may reveal alternative avenues of research in order to identify potential novel therapeutic targets for disease modifying strategies. The correlation between α-synuclein burden and Parkinson's disease pathology has led to the hypothesis that α-synuclein aggregation produces toxicity through a gain-of-function mechanism. However, in this review, we discuss data supporting the alternative hypothesis that the aggregation of α-synuclein results in toxicity because of loss of necessary α-synuclein function at the presynaptic terminal, following sequestration of functional forms of α-synuclein into aggregates.
authors: Department of Translational Science and Molecular Medicine, College of Human Medicine, Michigan State University, Grand Rapids, Michigan, USA.
authors: Matthew J
authors: MJ
authors: Benskey
authors: Department of Biomedical Sciences, Center of Emphasis in Neuroscience, Paul L. Foster School of Medicine, Texas Tech University of the Health Sciences El Paso, El Paso, Texas, USA.
authors: Ruth G
authors: RG
authors: Perez
authors: Department of Translational Science and Molecular Medicine, College of Human Medicine, Michigan State University, Grand Rapids, Michigan, USA.|Hauenstein Neuroscience Center, Mercy Health Saint Mary's, Grand Rapids, Michigan, USA.
authors: Fredric P
authors: FP
authors: Manfredsson
mesh_terms: D000818:Animals; D000978:Antiparkinson Agents / Q000494:pharmacology; D006801:Humans; D009474:Neurons / Q000187:drug effects / Q000473:pathology*; D010300:Parkinson Disease / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology*; D051844:alpha-Synuclein / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*
chemical_list: D000978:Antiparkinson Agents; D051844:alpha-Synuclein
keywords: Lewy body; Parkinson's disease; alpha-synuclein; dopamine; substantia nigra; synucleinopathy