Nerve Tissue Proteins

Publication Title: 
Aging Cell

Molecular advances of the past decade have led to the discovery of a myriad of 'aging genes' (methuselah, Indy, InR, Chico, superoxide dismutase) that extend Drosophila lifespan by up to 85%. Despite this life extension, these mutants are no longer lived than at least some recently wild-caught strains. Typically, long-lived mutants are identified in relatively short-lived genetic backgrounds, and their effects are rarely tested in genetic backgrounds other than the one in which they were isolated or derived.

Author(s): 
Spencer, Christine C.
Howell, Christine E.
Wright, Amber R.
Promislow, Daniel E. L.
Publication Title: 
Proceedings of the National Academy of Sciences of the United States of America

In investigating the role of metal ions in the pathogenesis of Huntington's disease, we examined the effects of clioquinol, a metal-binding compound currently in clinical trials for Alzheimer's disease treatment, on mutant huntingtin-expressing cells. We found that PC12 cells expressing polyglutamine-expanded huntingtin exon 1 accumulated less mutant protein and showed decreased cell death when treated with clioquinol. This effect was polyglutamine-length-specific and did not alter mRNA levels or protein degradation rates.

Author(s): 
Nguyen, Trent
Hamby, Aaron
Massa, Stephen M.
Publication Title: 
Nature Cell Biology

Protein ubiquitylation is a key post-translational control mechanism contributing to different physiological processes, such as signal transduction and ageing. The size and linkage of a ubiquitin chain, which determines whether a substrate is efficiently targeted for proteasomal degradation, is determined by the interplay between ubiquitylation and deubiquitylation. A conserved factor that orchestrates distinct substrate-processing co-regulators in diverse species is the ubiquitin-selective chaperone CDC-48 (also known as p97).

Author(s): 
Kuhlbrodt, Kirsten
Janiesch, Philipp Christoph
Kevei, …va
Segref, Alexandra
Barikbin, Roja
Hoppe, Thorsten
Publication Title: 
NestlÈ Nutrition Workshop Series. Paediatric Programme

Insulin and insulin-like signaling regulate survival and lifespan in a variety of animal species, from nematodes and flies to higher vertebrates and mammals. Recently, it was shown that brain IGF-I receptor and brain IRS2 control mammalian lifespan, and that this occurs through neuroendocrine mechanisms, control of energy metabolism and modified stress resistance. Furthermore, it was demonstrated that insulin receptor substrate molecules are implicated downstream of insulin and IGF receptors in the extension of lifespan.

Author(s): 
Holzenberger, Martin
Publication Title: 
Cell

Both poikilotherms and homeotherms live longer at lower body temperatures, highlighting a general role of temperature reduction in lifespan extension. However, the underlying mechanisms remain unclear. One prominent model is that cold temperatures reduce the rate of chemical reactions, thereby slowing the rate of aging. This view suggests that cold-dependent lifespan extension is simply a passive thermodynamic process. Here, we challenge this view in C. elegans by showing that genetic programs actively promote longevity at cold temperatures.

Author(s): 
Xiao, Rui
Zhang, Bi
Dong, Yongming
Gong, Jianke
Xu, Tao
Liu, Jianfeng
Xu, X. Z. Shawn
Publication Title: 
Human Molecular Genetics

The CISD2 gene, which is an evolutionarily conserved novel gene, encodes a transmembrane protein primarily associated with the mitochondrial outer membrane. Significantly, the CISD2 gene is located within the candidate region on chromosome 4q where a genetic component for human longevity has been mapped. Previously, we have shown that Cisd2 deficiency shortens lifespan resulting in premature aging in mice. Additionally, an age-dependent decrease in Cisd2 expression has been detected during normal aging.

Author(s): 
Wu, Chia-Yu
Chen, Yi-Fan
Wang, Chih-Hao
Kao, Cheng-Heng
Zhuang, Hui-Wen
Chen, Chih-Cheng
Chen, Liang-Kung
Kirby, Ralph
Wei, Yau-Huei
Tsai, Shih-Feng
Tsai, Ting-Fen
Publication Title: 
Nature Communications

It is hypothesized that a common underlying mechanism links multiple neurodegenerative disorders. Here we show that transitional endoplasmic reticulum ATPase (TERA)/valosin-containing protein (VCP)/p97 directly binds to multiple polyglutamine disease proteins (huntingtin, ataxin-1, ataxin-7 and androgen receptor) via polyglutamine sequence. Although normal and mutant polyglutamine proteins interact with TERA/VCP/p97, only mutant proteins affect dynamism of TERA/VCP/p97.

Author(s): 
Fujita, Kyota
Nakamura, Yoko
Oka, Tsutomu
Ito, Hikaru
Tamura, Takuya
Tagawa, Kazuhiko
Sasabe, Toshikazu
Katsuta, Asuka
Motoki, Kazumi
Shiwaku, Hiroki
Sone, Masaki
Yoshida, Chisato
Katsuno, Masahisa
Eishi, Yoshinobu
Murata, Miho
Taylor, J. Paul
Wanker, Erich E.
Kono, Kazuteru
Tashiro, Satoshi
Sobue, Gen
La Spada, Albert R.
Okazawa, Hitoshi
Publication Title: 
Nature Chemical Biology

In polyglutamine (polyQ) diseases, only certain neurons die, despite widespread expression of the offending protein. PolyQ expansion may induce neurodegeneration by impairing proteostasis, but protein aggregation and toxicity tend to confound conventional measurements of protein stability. Here, we used optical pulse labeling to measure effects of polyQ expansions on the mean lifetime of a fragment of huntingtin, the protein that causes Huntington's disease, in living neurons.

Author(s): 
Tsvetkov, Andrey S.
Arrasate, Montserrat
Barmada, Sami
Ando, D. Michael
Sharma, Punita
Shaby, Benjamin A.
Finkbeiner, Steven
Publication Title: 
Neuromolecular Medicine

Emerging lines of evidence suggest a relationship between amyotrophic lateral sclerosis (ALS) and protein sumoylation. Multiple studies have demonstrated that several of the proteins involved in the pathogenesis of ALS, including superoxide dismutase 1, fused in liposarcoma, and TAR DNA-binding protein 43 (TDP-43), are substrates for sumoylation.

Author(s): 
Foran, Emily
Rosenblum, Lauren
Bogush, Alexey I.
Trotti, Davide
Publication Title: 
Genes & Development

The Spt-Ada-Gcn5-acetyltransferase (SAGA) chromatin-modifying complex possesses acetyltransferase and deubiquitinase activities. Within this modular complex, Ataxin-7 anchors the deubiquitinase activity to the larger complex. Here we identified and characterized Drosophila Ataxin-7 and found that reduction of Ataxin-7 protein results in loss of components from the SAGA complex.

Author(s): 
Mohan, Ryan D.
Dialynas, George
Weake, Vikki M.
Liu, Jianqi
Martin-Brown, Skylar
Florens, Laurence
Washburn, Michael P.
Workman, Jerry L.
Abmayr, Susan M.

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