排序方式: 共有3条查询结果,搜索用时 15 毫秒
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Albert Lee Stephanie L. Rayner Serene S. L. Gwee Alana De Luca Hamideh Shahheydari Vinod Sundaramoorthy Audrey Ragagnin Marco Morsch Rowan Radford Jasmin Galper Sarah Freckleton Bingyang Shi Adam K. Walker Emily K. Don Nicholas J. Cole Shu Yang Kelly L. Williams Justin J. Yerbury Ian P. Blair Julie D. Atkin Mark P. Molloy Roger S. Chung 《Cellular and molecular life sciences : CMLS》2018,75(2):335-354
Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are fatal neurodegenerative disorders that have common molecular and pathogenic characteristics, such as aberrant accumulation and ubiquitylation of TDP-43; however, the mechanisms that drive this process remain poorly understood. We have recently identified CCNF mutations in familial and sporadic ALS and FTD patients. CCNF encodes cyclin F, a component of an E3 ubiquitin–protein ligase (SCFcyclin F) complex that is responsible for ubiquitylating proteins for degradation by the ubiquitin–proteasome system. In this study, we examined the ALS/FTD-causing p.Ser621Gly (p.S621G) mutation in cyclin F and its effect upon downstream Lys48-specific ubiquitylation in transfected Neuro-2A and SH-SY5Y cells. Expression of mutant cyclin FS621G caused increased Lys48-specific ubiquitylation of proteins in neuronal cells compared to cyclin FWT. Proteomic analysis of immunoprecipitated Lys48-ubiquitylated proteins from mutant cyclin FS621G-expressing cells identified proteins that clustered within the autophagy pathway, including sequestosome-1 (p62/SQSTM1), heat shock proteins, and chaperonin complex components. Examination of autophagy markers p62, LC3, and lysosome-associated membrane protein 2 (Lamp2) in cells expressing mutant cyclin FS621G revealed defects in the autophagy pathway specifically resulting in impairment in autophagosomal–lysosome fusion. This finding highlights a potential mechanism by which cyclin F interacts with p62, the receptor responsible for transporting ubiquitylated substrates for autophagic degradation. These findings demonstrate that ALS/FTD-causing mutant cyclin FS621G disrupts Lys48-specific ubiquitylation, leading to accumulation of substrates and defects in the autophagic machinery. This study also demonstrates that a single missense mutation in cyclin F causes hyper-ubiquitylation of proteins that can indirectly impair the autophagy degradation pathway, which is implicated in ALS pathogenesis. 相似文献
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Wyatt AR Yerbury JJ Berghofer P Greguric I Katsifis A Dobson CM Wilson MR 《Cellular and molecular life sciences : CMLS》2011,68(23):3919-3931
The extracellular deposition of misfolded proteins is a characteristic of many debilitating age-related disorders. However,
little is known about the specific mechanisms that act to suppress this process in vivo. Clusterin (CLU) is an extracellular
chaperone that forms stable and soluble complexes with misfolded client proteins. Here we explore the fate of complexes formed
between CLU and misfolded proteins both in vitro and in a living organism. We show that proteins injected into rats are cleared
more rapidly from circulation when complexed with CLU as a result of their more efficient localization to the liver and that
this clearance is delayed by pre-injection with the scavenger receptor inhibitor fucoidan. The CLU–client complexes were found
to bind preferentially, in a fucoidan-inhibitable manner, to human peripheral blood monocytes and isolated rat hepatocytes
and in the latter cell type were internalized and targeted to lysosomes for degradation. The data suggest, therefore, that
CLU plays a key role in an extracellular proteostasis system that recognizes, keeps soluble, and then rapidly mediates the
disposal of misfolded proteins. 相似文献
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Vinod Sundaramoorthy Adam K. Walker Justin Yerbury Kai Ying Soo Manal A. Farg Vy Hoang Rafaa Zeineddine Damian Spencer Julie D. Atkin 《Cellular and molecular life sciences : CMLS》2013,70(21):4181-4195
Amyotrophic lateral sclerosis (ALS) is a fatal and rapidly progressing neurodegenerative disorder and the majority of ALS is sporadic, where misfolding and aggregation of Cu/Zn-superoxide dismutase (SOD1) is a feature shared with familial mutant-SOD1 cases. ALS is characterized by progressive neurospatial spread of pathology among motor neurons, and recently the transfer of extracellular, aggregated mutant SOD1 between cells was demonstrated in culture. However, there is currently no evidence that uptake of SOD1 into cells initiates neurodegenerative pathways reminiscent of ALS pathology. Similarly, whilst dysfunction to the ER–Golgi compartments is increasingly implicated in the pathogenesis of both sporadic and familial ALS, it remains unclear whether misfolded, wildtype SOD1 triggers ER–Golgi dysfunction. In this study we show that both extracellular, native wildtype and mutant SOD1 are taken up by macropinocytosis into neuronal cells. Hence uptake does not depend on SOD1 mutation or misfolding. We also demonstrate that purified mutant SOD1 added exogenously to neuronal cells inhibits protein transport between the ER–Golgi apparatus, leading to Golgi fragmentation, induction of ER stress and apoptotic cell death. Furthermore, we show that extracellular, aggregated, wildtype SOD1 also induces ER–Golgi pathology similar to mutant SOD1, leading to apoptotic cell death. Hence extracellular misfolded wildtype or mutant SOD1 induce dysfunction to ER–Golgi compartments characteristic of ALS in neuronal cells, implicating extracellular SOD1 in the spread of pathology among motor neurons in both sporadic and familial ALS. 相似文献
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