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- Title
α-Synuclein is part of a diverse and highly conserved interaction network that includes PARK9 and manganese toxicity.
- Authors
Gitler, Aaron D.; Chesi, Alessandra; Geddie1, Melissa L.; Strathearn, Katherine E.; Hamamichi, Shusei; Hill, Kathryn J.; Caldwell, Kim A.; Caldwell, Guy A.; Cooper, Antony A.; Rochet, Jean-Christophe; Lindquist, Susan
- Abstract
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. α-Synuclein (α-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 α-syn and the yeast ortholog of the PD-linked gene ATP13A2 (also known as PARK9). Dopaminergic neuron loss caused by α-syn overexpression in animal and neuronal PD models is rescued by coexpression of PARK9. Further, knockdown of the ATP13A2 ortholog in Caenorhabditis elegans enhances α-syn misfolding. These data provide a direct functional connection between α-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 (α-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 α-syn–induced neuron loss in animals, establishing a diverse, highly conserved interaction network for α-syn.
- Publication
Nature Genetics, 2009, Vol 41, Issue 3, p308
- ISSN
1061-4036
- Publication type
Academic Journal
- DOI
10.1038/ng.300