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Impairment of the ubiquitin proteasome system by protein aggregation
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TLDR
It is reported that protein aggregation directly impaired the function of the ubiquitin-proteasome system, suggesting a potential mechanism linking protein aggregation to cellular disregulation and cell death.Abstract:
Intracellular deposition of aggregated and ubiquitylated proteins is a prominent cytopathological feature of most neurodegenerative disorders. Whether protein aggregates themselves are pathogenic or are the consequence of an underlying molecular lesion is unclear. Here, we report that protein aggregation directly impaired the function of the ubiquitin-proteasome system. Transient expression of two unrelated aggregation-prone proteins, a huntingtin fragment containing a pathogenic polyglutamine repeat and a folding mutant of cystic fibrosis transmembrane conductance regulator, caused nearly complete inhibition of the ubiquitin-proteasome system. Because of the central role of ubiquitin-dependent proteolysis in regulating fundamental cellular events such as cell division and apoptosis, our data suggest a potential mechanism linking protein aggregation to cellular disregulation and cell death.read more
Citations
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Autophagy: Renovation of Cells and Tissues
Noboru Mizushima,Masaaki Komatsu +1 more
TL;DR: It is explored how recent mouse models in combination with advances in human genetics are providing key insights into how the impairment or activation of autophagy contributes to pathogenesis of diverse diseases, from neurodegenerative diseases such as Parkinson disease to inflammatory disorders such as Crohn disease.
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Protein folding and misfolding
TL;DR: The manner in which a newly synthesized chain of amino acids transforms itself into a perfectly folded protein depends both on the intrinsic properties of the amino-acid sequence and on multiple contributing influences from the crowded cellular milieu.
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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.
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Loss of autophagy in the central nervous system causes neurodegeneration in mice
Masaaki Komatsu,Satoshi Waguri,Satoshi Waguri,Tomoki Chiba,Shigeo Murata,Junichi Iwata,Junichi Iwata,Isei Tanida,Takashi Ueno,Masato Koike,Yasuo Uchiyama,Eiki Kominami,Keiji Tanaka +12 more
TL;DR: It is found that mice lacking Atg7 specifically in the central nervous system showed behavioural defects, including abnormal limb-clasping reflexes and a reduction in coordinated movement, and died within 28 weeks of birth, and that impairment of autophagy is implicated in the pathogenesis of neurodegenerative disorders involving ubiquitin-containing inclusion bodies.
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Protein aggregation and neurodegenerative disease.
TL;DR: There is increased understanding of the pathways involved in protein aggregation, and some recent clues have emerged as to the molecular mechanisms of cellular toxicity, leading to approaches toward rational therapeutics.
References
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Journal ArticleDOI
Mutations in the parkin gene cause autosomal recessive juvenile parkinsonism
Tohru Kitada,Shuichi Asakawa,Nobutaka Hattori,Hiroto Matsumine,Yasuhiro Yamamura,Shinsei Minoshima,Masayuki Yokochi,Yoshikuni Mizuno,Nobuyoshi Shimizu +8 more
TL;DR: Mutations in the newly identified gene appear to be responsible for the pathogenesis of Autosomal recessive juvenile parkinsonism, and the protein product is named ‘Parkin’.
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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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The ubiquitin pathway in Parkinson's disease
Elisabeth Leroy,Rebecca Boyer,Georg Auburger,Barbara Leube,Gudrun Ulm,Eva Mezey,G Harta,Michael J. Brownstein,Sobhanadditya Jonnalagada,Tanya Chernova,Anindya Dehejia,Christian Lavedan,Thomas Gasser,Peter J. Steinbach,Keith D. Wilkinson,Mihael H. Polymeropoulos +15 more
TL;DR: It is shown that in a German family with Parkinson's disease a missense mutation in the ubiquitin carboxy-terminal hydrolase L1 (UCH-L1) gene causes a partial loss of the catalytic activity of this thiol protease, which could lead to aberrations in the proteolytic pathway and aggregation of proteins.
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Glutamine Repeats and Neurodegeneration
Huda Y. Zoghbi,Harry T. Orr +1 more
TL;DR: A model for pathogenesis that illuminates the unifying features of these polyglutamine disorders is concluded, and may prove relevant to other neurodegenerative disorders as well.
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Glutamine repeats as polar zippers: their possible role in inherited neurodegenerative diseases
TL;DR: Molecular modeling followed by optical, electron, and x-ray diffraction studies of a synthetic poly(L-glutamine) shows that it forms beta-sheets strongly held together by hydrogen bonds.