Chung CY, Khurana V, Auluck PK, Tardiff DF, Mazzulli JR, Soldner F, Baru V, Lou Y, Freyzon Y, Cho S, Mungenast AE, Muffat J, Mitalipova M, Pluth MD, Jui NT, Schüle B, Lippard SJ, Tsai LH, Krainc D, Buchwald SL, Jaenisch R, Lindquist S.
Identification and Rescue of α-Synuclein Toxicity in Parkinson Patient-Derived Neurons.
Science. 2013 Nov 22;342(6161):983-7.
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Chung and colleagues elegantly demonstrate in this article how a familiar Parkinson mutation, the A53T variant of α-synuclein, causes nitrosative stress that affects the secretory transport of several neuronal proteins in iPS-derived neurons. This phenomenon was rescued by either expression of suppressors of endoplasmic reticulum-associated protein degradation (ERAD), like the ubiquitin ligase Hdr1, or by small compound inhibitors of NAB2. Of note, ER stress has been implicated in other neurodegenerative diseases, such as Alzheimer’s and prion disease. This study is elaborate and provides an in-depth view of the effects of nitrosative stress on core cellular functions such as protein transport and degradation.
The questions that remain are how nitric oxide controls these events and what its targets are. In the case of PD, nitration and dityrosine modification of α-synuclein itself have been found in synucleinopathy lesions (1–3). Therefore, it is of interest to know if α-synuclein itself, or others, are modified by nitric oxide in PD.
Giasson BI, Duda JE, Murray IV, Chen Q, Souza JM, Hurtig HI, Ischiropoulos H, Trojanowski JQ, Lee VM.
Oxidative damage linked to neurodegeneration by selective alpha-synuclein nitration in synucleinopathy lesions.
Science. 2000 Nov 3;290(5493):985-9.
Souza JM, Giasson BI, Chen Q, Lee VM, Ischiropoulos H.
Dityrosine cross-linking promotes formation of stable alpha -synuclein polymers. Implication of nitrative and oxidative stress in the pathogenesis of neurodegenerative synucleinopathies.
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Duda JE, Giasson BI, Chen Q, Gur TL, Hurtig HI, Stern MB, Gollomp SM, Ischiropoulos H, Lee VM, Trojanowski JQ.
Widespread nitration of pathological inclusions in neurodegenerative synucleinopathies.
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