Editors' ChoiceParkinson’s Disease

Targeting ER Stress in Parkinson's Disease

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Science Translational Medicine  06 Nov 2013:
Vol. 5, Issue 210, pp. 210ec183
DOI: 10.1126/scitranslmed.3007932

Neurodegenerative diseases are a major health concern for our aging population. It has been challenging to model these diseases and identify effective treatment strategies. Monogenic forms of neurodegenerative diseases have revealed some important targets for study. For example, the A53T mutation in the α-synuclein (α-syn) protein results in a highly penetrant form of Parkinson’s disease (PD) in which patients develop the disease at a young age. α-Syn is involved in vesicular trafficking in cells, and the accumulation of misfolded α-syn leads to the formation of Lewy body inclusions in the brain, neuronal dysfunction, and neuronal death. However, little is known about the early pathogenic mechanisms that underlie α-syn–induced toxicity in neurons.

Over the past several years, Lindquist and colleagues have used genetic screens in yeast to identify several potent modifiers of α-syn toxicity. The authors now report that nitrosative stress, ER (endoplasmic reticulum) stress, and the accumulation of ER-associated degradation substrates are central processes in α-syn–mediated toxicity. Nitrosative stress is a process in which reactive nitric oxide (NO) species alter cellular proteins, lipids, and DNA. A genetic screen in yeast revealed that increased expression of Fzf1, a regulator of nitrosative stress responses, decreased α-syn–induced toxicity and protein nitration. Additionally, the authors demonstrated that increased NO in the context of elevated α-syn resulted in increased ER stress that impaired trafficking of proteins and the accumulation of ER degradation substrates. Having defined early pathogenic processes underlying α-syn–mediated toxicity in yeast, the authors turned to a human induced pluripotent stem cell (iPSC) model of PD that harbors the A53T α-syn mutation. Remarkably, the cellular phenotype identified in yeast involving increased nitrotyrosine and ER stress was also seen in the mutant iPSC–derived neurons and was evident in brain tissue from PD patients with the A53T mutation. Last, the authors demonstrated that a small molecule, an N-arylbenzimidazole called NAB-2 discovered in a chemical genetic screen, rescued the disease phenotypes in yeast and iPSC-derived neurons from PD patients.

These studies provide a new mechanistic understanding of the cellular processes underlying α–syn-induced neuronal death and provide a target to block these processes in human neurons. Future work will test the safety and efficacy of NAB-2 in animal models of PD.

C. Y. Chung et al., Identification and rescue of α-synuclein toxicity in Parkinson patient–derived neurons. Science, published online 24 October 2013 (PMID: 24158904). [Abstract]

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