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Gitler AD, Chesi A, Geddie ML, Strathearn KE, Hamamichi S, Hill KJ, Caldwell KA, Caldwell GA, Cooper AA, Rochet JC, Lindquist S. Alpha-synuclein is part of a diverse and highly conserved interaction network that includes PARK9 and manganese toxicity. Nat Genet. 2009 Mar;41(3):308-15. PubMed.
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Harvard Medical School, Brigham and Women's Hospital
Lindquist and collaborators show that overexpression of orthologs of the familial PD gene PARK9 in yeast and worm, and overexpression of human PARK9 in rat primary midbrain cultures suppresses α-synuclein (SNCA) toxicity in theses models. The genetic interaction between the two PD genes SNCA (PARK1) and ATP13A2 (PARK9) is exciting. This provocative observation suggests for the first time that these two previously unconnected PD genes may be involved in one single disease pathway.
This raises a number of questions: What precisely is this pathway and what exactly are the roles α-synuclein and ATP13A2 play in it? Is it ER-to-Golgi transport as the authors hint at, or could it be a lysosomal or other process? Unfortunately, little is known about the biological role of ATP13A2 other than its classification as a P-class ion pump and that it seems to localize to lysosomal membranes in COS7 cells. It will be important to clarify the subcellular localization and the biochemistry of this interaction, and substantiate the relevance of this link between SNCA and ATP13A2 for the human disease, in human dopamine cells, and in the substantia nigra of patients with PD.
Exposure to manganese-containing fumes may make welders more prone to develop PD. In a second part of the study, Gitler et al. speculate about an additional role for PARK9 in this process. They indicate that yeast ATP13A2 modulates sensitivity of yeast cells to manganese exposure. This is an interesting hypothesis—but a lot more research is needed to clinch this.
View all comments by Clemens ScherzerCould PARK9 and manganese toxicity have a role in ALS?
View all comments by robert ventulloUniversity of Toronto
In this work, Susan Lindquist and colleagues from the Whitehead Institute reported a functional interaction between α-synuclein and the yeast ortholog of the Parkinson gene ATP13A2. Moreover, they showed that a knockdown of the corresponding ortholog in C. elegans enhanced α-synuclein misfolding. Finally, they demonstrated that the yeast ortholog could protect cells from manganese toxicity. This elegant work has, for the first time, demonstrated a functional link between two different Parkinson genes in combination with a recognized environmental factor—it contributes to an increased understanding of the complex mechanisms behind Parkinson disease.
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