The contribution of alpha synuclein to neuronal survival and function – Implications for Parkinson's disease

<jats:title>Abstract</jats:title><jats:sec><jats:label/><jats:p>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 (<jats:styled-content style="fixed-case">PD</jats:styled-content>) is arguably the best characterized. Aggregated α‐syn is the primary component of Lewy bodies, the defining pathological feature of<jats:styled-content style="fixed-case">PD</jats:styled-content>, while mutations or multiplications in the α‐syn gene result in familial<jats:styled-content style="fixed-case">PD</jats:styled-content>. The high correlation between α‐syn burden and<jats:styled-content style="fixed-case">PD</jats:styled-content>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<jats:styled-content style="fixed-case">PD</jats:styled-content>and the knowledge gained from current α‐syn‐based animal models of<jats:styled-content style="fixed-case">PD</jats:styled-content>. 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<jats:styled-content style="fixed-case">PD</jats:styled-content>. By providing an alternative perspective on the etiopathogenesis of<jats:styled-content style="fixed-case">PD</jats:styled-content>and synucleinopathies, this may reveal alternative avenues of research in order to identify potential novel therapeutic targets for disease modifying strategies.</jats:p></jats:sec><jats:sec><jats:label/><jats:p><jats:boxed-text content-type="graphic" position="anchor"><jats:graphic xmlns:xlink="http://www.w3.org/1999/xlink" mimetype="image/png" position="anchor" specific-use="enlarged-web-image" xlink:href="graphic/jnc13570-fig-0004-m.png"><jats:alt-text>image</jats:alt-text></jats:graphic></jats:boxed-text>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.</jats:p></jats:sec>