Signaling, polyubiquitination, trafficking, and inclusions: sequestosome 1/p62's role in neurodegenerative disease.
Marie W. Wooten,Xiao Hu,J. Ramesh Babu,M. Lamar Seibenhener,Thangiah Geetha,Michael G. Paine,Michael C. Wooten +6 more
TLDR
In this paper, the role of p62's role in signaling, aggregation, and inclusion formation, and specifically as a possible contributor to Alzheimer's disease, is reviewed and p62 is used as a potential target for the development of therapeutics and as a disease biomarker.Abstract:
Aggregated misfolded proteins are hallmarks of most neurodegenerative diseases In a chronic disease state, including pathologic situations of oxidative stress, these proteins are sequestered into inclusions Accumulation of aggregated proteins can be prevented by chaperones, or by targeting their degradation to the UPS If the accumulation of these proteins exceeds their degradation, they may impair the function of the proteasome Alternatively, the function of the proteasome may be preserved by directing aggregated proteins to the autophagy-lysosome pathway for degradation Sequestosome 1/p62 has recently been shown to interact with polyubiquitinated proteins through its UBA domain and may direct proteins to either the UPS or autophagosome P62 is present in neuronal inclusions of individuals with Alzheimer's disease and other neurodegenerative diseases Herein, we review p62's role in signaling, aggregation, and inclusion formation, and specifically as a possible contributor to Alzheimer's disease The use of p62 as a potential target for the development of therapeutics and as a disease biomarker is also discussedread more
Citations
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Autophagy: process and function
TL;DR: In this review, the process of autophagy is summarized, and the role of autophileagy is discussed in a process-based manner.
Journal ArticleDOI
Homeostatic Levels of p62 Control Cytoplasmic Inclusion Body Formation in Autophagy-Deficient Mice
Masaaki Komatsu,Satoshi Waguri,Masato Koike,Yu-shin Sou,Yu-shin Sou,Takashi Ueno,Taichi Hara,Noboru Mizushima,Junichi Iwata,Junichi Iwata,Junji Ezaki,Shigeo Murata,Jun Hamazaki,Yasumasa Nishito,Shun-ichiro Iemura,Tohru Natsume,Toru Yanagawa,Junya Uwayama,Eiji Warabi,Hiroshi Yoshida,Tetsuro Ishii,Akira Kobayashi,Masayuki Yamamoto,Zhenyu Yue,Yasuo Uchiyama,Eiki Kominami,Keiji Tanaka +26 more
TL;DR: The findings highlight the unexpected role of homeostatic level of p62, which is regulated by autophagy, in controlling intracellular inclusion body formation, and indicate that the pathologic process associated with autophagic deficiency is cell-type specific.
Journal ArticleDOI
Autophagy Inhibition Compromises Degradation of Ubiquitin-Proteasome Pathway Substrates
TL;DR: It is shown that autophagy inhibition increases levels of proteasome substrates, which will lead to increased levels of short-lived regulatory proteins, like p53, as well as the accumulation of aggregation-prone proteins, with predicted deleterious consequences.
Journal ArticleDOI
p62 positive, TDP-43 negative, neuronal cytoplasmic and intranuclear inclusions in the cerebellum and hippocampus define the pathology of C9orf72-linked FTLD and MND/ALS
Safa Al-Sarraj,Andrew T. King,Claire Troakes,Bradley N. Smith,Satomi Maekawa,Istvan Bodi,Boris Rogelj,Ammar Al-Chalabi,Tibor Hortobágyi,Christopher Shaw +9 more
TL;DR: In this paper, a subset of TDP-43 proteinopathy patients who have unusual and abundant p62 positive, TDP43 negative inclusions in the cerebellum and hippocampus were found to carry hexanucleotide repeat expansion in C9orf72.
Journal ArticleDOI
A small molecule inhibitor of inducible heat shock protein 70.
TL;DR: The data demonstrate that PES disrupts actions of HSP70 in multiple cell signaling pathways, offering an opportunity to better understand the diverse functions of this molecular chaperone and also to aid in the development of new cancer therapies.
References
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Journal ArticleDOI
The Amyloid Hypothesis of Alzheimer's Disease: Progress and Problems on the Road to Therapeutics
John Hardy,Dennis J. Selkoe +1 more
TL;DR: It has been more than 10 years since it was first proposed that the neurodegeneration in Alzheimer's disease (AD) may be caused by deposition of amyloid β-peptide in plaques in brain tissue and the rest of the disease process is proposed to result from an imbalance between Aβ production and Aβ clearance.
Journal ArticleDOI
The Ubiquitin-Proteasome Proteolytic Pathway: Destruction for the Sake of Construction
TL;DR: It is clear now that degradation of cellular proteins is a highly complex, temporally controlled, and tightly regulated process that plays major roles in a variety of basic pathways during cell life and death as well as in health and disease.
Journal ArticleDOI
p62/SQSTM1 forms protein aggregates degraded by autophagy and has a protective effect on huntingtin-induced cell death
Geir Bjørkøy,Trond Lamark,Andreas Brech,Heidi Outzen,Maria Perander,Aud Øvervatn,Harald Stenmark,Terje Johansen +7 more
TL;DR: In this article, the polyubiquitin-binding protein p62/SQSTM1 has been shown to be involved in linking polyUBiquitinated protein aggregates to the autophagy machinery.
Journal ArticleDOI
Autophagy in Health and Disease: A Double-Edged Sword
TL;DR: Identifying the autophagy genes in yeast and finding orthologs in other organisms reveals the conservation of the mechanism in eukaryotes and allows the use of molecular genetics and biology in different model systems to study this process.
Journal ArticleDOI
Aggresomes: A Cellular Response to Misfolded Proteins
TL;DR: The intracellular fate of cystic fibrosis transmembrane conductance regulator (CFTR) is investigated and it is demonstrated that undegraded CFTR molecules accumulate at a distinct pericentriolar structure which is termed the aggresome.
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