alpha-Synuclein is part of a diverse and highly conserved interaction network that includes PARK9 and manganese toxicity

作者：Gitler Aaron D; Chesi Alessandra; Geddie Melissa L; Strathearn Katherine E; Hamamichi Shusei; Hill Kathryn J; Caldwell Kim A; Caldwell Guy A; Cooper Antony A; Rochet Jean Christophe; Lindquist Susan^*

来源：Nature Genetics, 2009, 41(3): 308-315.

DOI：10.1038/ng.300

Parkinson's disease (PD), dementia with Lewy bodies and multiple system atrophy, collectively referred to as synucleinopathies, are associated with a diverse group of genetic and environmental susceptibilities. The best studied of these is PD. alpha-Synuclein (alpha-syn) has a key role in the pathogenesis of both familial and sporadic PD, but evidence linking it to other predisposition factors is limited. Here we report a strong genetic interaction between alpha-syn and the yeast ortholog of the PD-linked gene ATP13A2 (also known as PARK9). Dopaminergic neuron loss caused by alpha-syn overexpression in animal and neuronal PD models is rescued by coexpression of PARK9. Further, knockdown of the ATP13A2 ortholog in Caenorhabditis elegans enhances alpha-syn misfolding. These data provide a direct functional connection between alpha-syn and another PD susceptibility locus. Manganese exposure is an environmental risk factor linked to PD and PD-like syndromes. We discovered that yeast PARK9 helps to protect cells from manganese toxicity, revealing a connection between PD genetics (alpha-syn and PARK9) and an environmental risk factor (PARK9 and manganese). Finally, we show that additional genes from our yeast screen, with diverse functions, are potent modifiers of alpha-syn-induced neuron loss in animals, establishing a diverse, highly conserved interaction network for alpha-syn.

• 出版日期2009-3
• 单位河北医科大学