Regulation of ATP13A2 Via PHD2-HIF1α Signaling Is Critical for Cellular Iron Homeostasis: Implications for Parkinson's Disease

Overview

Journal J Neurosci

Specialty Neurology

Date 2016 Jan 29

PMID 26818499

Citations 31

Authors

Subramanian Rajagopalan

Anand Rane

Shankar J Chinta

Julie K Andersen

Affiliations

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Abstract

Significance Statement: Reductions in PHD2 activity within dopaminergic neurons in vivo and in cultured human induced pluripotent stem cell-derived neurons protects against mitochondrial stress-induced neurotoxicity. Protective effects are dependent on downstream HIF-1α expression. Knockdown of ATP13A2, a gene linked to a rare juvenile form of Parkinson's disease and recently identified as a novel HIF1α target, was found to abrogate maintenance of cellular iron homeostasis and neuronal viability elicited by PHD2 inhibition in vivo and in cultured dopaminergic cells under conditions of mitochondrial stress. Mechanistically, this was due to ATP13A2's role in maintaining lysosomal iron stores. This constitutes a novel mechanism by which alterations in ATP13A2 activity may be driving PD-related neuropathology.

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