Abstract:
:Expression of misfolded protein in cultured cells frequently leads to the formation of juxtanuclear inclusions that have been termed 'aggresomes'. Aggresome formation is an active cellular response that involves trafficking of the offending protein along microtubules, reorganization of intermediate filaments and recruitment of components of the ubiquitin proteasome system. Whether aggresomes are benevolent or noxious is unknown, but they are of particular interest because of the appearance of similar inclusions in protein deposition diseases. Here we present evidence that aggresomes serve a cytoprotective function and are associated with accelerated turnover of mutant proteins. We show that mutant androgen receptor (AR), the protein responsible for X-linked spinobulbar muscular atrophy, forms insoluble aggregates and is toxic to cultured cells. Mutant AR was also found to form aggresomes in a process distinct from aggregation. Molecular and pharmacological interventions were used to disrupt aggresome formation, revealing their cytoprotective function. Aggresome-forming proteins were found to have an accelerated rate of turnover, and this turnover was slowed by inhibition of aggresome formation. Finally, we show that aggresome-forming proteins become membrane-bound and associate with lysosomal structures. Together, these findings suggest that aggresomes are cytoprotective, serving as cytoplasmic recruitment centers to facilitate degradation of toxic proteins.
journal_name
Hum Mol Genetjournal_title
Human molecular geneticsauthors
Taylor JP,Tanaka F,Robitschek J,Sandoval CM,Taye A,Markovic-Plese S,Fischbeck KHdoi
10.1093/hmg/ddg074subject
Has Abstractpub_date
2003-04-01 00:00:00pages
749-57issue
7eissn
0964-6906issn
1460-2083journal_volume
12pub_type
杂志文章abstract::Genome-wide scans for linkage of chromosome regions to type 1 diabetes in affected sib pair families have revealed that the major susceptibility locus resides within the major histocompatibility complex (MHC) on chromosome 6p21 (lambda S = 2.4). It is recognized that the MHC contains multiple susceptibility loci (refe...
journal_title:Human molecular genetics
pub_type: 杂志文章,评审
doi:10.1093/hmg/5.supplement_1.1443
更新日期:1996-01-01 00:00:00
abstract::Primary open-angle glaucoma (POAG) is a complex disorder characterized by a progressive and treatable degeneration of the optic nerve. TIGR/myocilin (MYOC) gene mutations are found in approximately 4% of all POAG patients. Populations with frequent founder effects, such as the French-Canadians, offer unique advantages...
journal_title:Human molecular genetics
pub_type: 杂志文章
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abstract::CHARGE syndrome is a multiple congenital anomaly disorder that leads to life-threatening birth defects, such as choanal atresia and cardiac malformations as well as multiple sensory impairments, that affect hearing, vision, olfaction and balance. CHARGE is caused by heterozygous mutations in CHD7, which encodes an ATP...
journal_title:Human molecular genetics
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abstract::Hidrotic ectodermal dysplasia (HED), Clouston type, is an autosomal dominant skin disorder which is most common in the French-Canadian population and is characterized by hair defects, nail dystrophy and palmoplantar hyperkeratosis. Biophysical and biochemical studies conducted in HED suggested a molecular abnormality ...
journal_title:Human molecular genetics
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更新日期:1996-04-01 00:00:00
abstract::The aim of this study was to investigate the possible role of STAT4 gene in the genetic predisposition to systemic sclerosis (SSc) susceptibility or clinical phenotype. A total of 1317 SSc patients [896 with limited cutaneous SSc (lcSSc) and 421 with diffuse cutaneous SSc (dcSSc)] and 3113 healthy controls, from an in...
journal_title:Human molecular genetics
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abstract::Biallelic loss-of-function mutations in the RNA-binding protein EIF4A3 cause Richieri-Costa-Pereira syndrome (RCPS), an autosomal recessive condition mainly characterized by craniofacial and limb malformations. However, the pathogenic cellular mechanisms responsible for this syndrome are entirely unknown. Here, we use...
journal_title:Human molecular genetics
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journal_title:Human molecular genetics
pub_type: 杂志文章
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更新日期:2014-02-15 00:00:00
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journal_title:Human molecular genetics
pub_type: 杂志文章
doi:10.1093/hmg/8.7.1245
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abstract::Degenerate primer pairs that include consensus sequences of evolutionary conserved portions of protein families (BLOCKs or ancient conserved regions) can be used to screen by polymerase chain reaction (PCR) for cognate cDNAs and YACs through much of phylogeny. Nine such primer pairs were developed, and five with sites...
journal_title:Human molecular genetics
pub_type: 杂志文章
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journal_title:Human molecular genetics
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abstract::Synapsin I (SynI) is a synaptic vesicle (SV) phosphoprotein playing multiple roles in synaptic transmission and plasticity by differentially affecting crucial steps of SV trafficking in excitatory and inhibitory synapses. SynI knockout (KO) mice are epileptic, and nonsense and missense mutations in the human SYN1 gene...
journal_title:Human molecular genetics
pub_type: 杂志文章
doi:10.1093/hmg/ddt071
更新日期:2013-06-01 00:00:00
abstract::The ATM gene is responsible for the autosomal recessive disorder ataxia-telangiectasia (A-T), characterized by cerebellar degeneration, immunodeficiency and cancer predisposition. A-T carriers were reported to be moderately cancer-prone. A wide variety of A-T mutations, most of which are unique to single families, wer...
journal_title:Human molecular genetics
pub_type: 杂志文章
doi:10.1093/hmg/5.12.2033
更新日期:1996-12-01 00:00:00
abstract::Release of amyloid beta (Abeta) from the amyloid precursor protein (APP) requires cleavages by beta- and gamma-secretases and plays a crucial role in Alzheimer's disease (AD) pathogenesis. Missense mutations in the APP gene causing familial AD are clustered around the beta-, alpha- and particular gamma-secretase cleav...
journal_title:Human molecular genetics
pub_type: 杂志文章
doi:10.1093/hmg/10.16.1665
更新日期:2001-08-01 00:00:00
abstract::The parent of origin-dependent expression of the IGF2 and H19 genes is controlled by the imprinting centre 1 (IC1) consisting in a methylation-sensitive chromatin insulator. Deletions removing part of IC1 have been found in patients affected by the overgrowth- and tumour-associated Beckwith-Wiedemann syndrome (BWS). T...
journal_title:Human molecular genetics
pub_type: 杂志文章
doi:10.1093/hmg/ddn031
更新日期:2008-05-15 00:00:00
abstract::Paraspeckles are nuclear bodies formed by a set of specialized proteins assembled on the long non-coding RNA NEAT1; they have a role in nuclear retention of hyperedited transcripts and are associated with response to cellular stress. Fused in sarcoma (FUS) protein, linked to a number of neurodegenerative disorders, is...
journal_title:Human molecular genetics
pub_type: 杂志文章
doi:10.1093/hmg/ddt622
更新日期:2014-05-01 00:00:00
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journal_title:Human molecular genetics
pub_type: 杂志文章
doi:10.1093/hmg/ddn288
更新日期:2008-10-15 00:00:00
abstract::The transcription factor SOX10 is mutated in the human neurocristopathy Waardenburg-Shah syndrome (WS4), which is characterized by enteric aganglionosis and pigmentation defects. SOX10 directly regulates genes expressed in neural crest lineages, including the enteric ganglia and melanocytes. Although some SOX10 target...
journal_title:Human molecular genetics
pub_type: 杂志文章
doi:10.1093/hmg/ddi442
更新日期:2006-01-15 00:00:00
abstract::Mitochondrial dysfunction plays an important role in the etiology of neurodegenerative diseases. However, the progressive nature of neuronal loss in genetic models of mitochondrial dysfunction suggests the presence of compensatory mechanisms promoting neuronal survival under these conditions. Here, we identified the e...
journal_title:Human molecular genetics
pub_type: 杂志文章
doi:10.1093/hmg/dds500
更新日期:2013-03-01 00:00:00
abstract::Saposin B derives from the multi-functional precursor, prosaposin, and functions as an activity enhancer for several glycosphingolipid (GSL) hydrolases. Mutations in saposin B present in humans with phenotypes resembling metachromatic leukodystrophy. To gain insight into saposin B's physiological functions, a specific...
journal_title:Human molecular genetics
pub_type: 杂志文章
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更新日期:2008-08-01 00:00:00
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journal_title:Human molecular genetics
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abstract::Facioscapulohumeral muscular dystrophy (FSHD) is an autosomal dominant neuromuscular disease that has been linked to deletions within a tandem array of 3.2 kb repeats adjacent to the telomere of 4q. These repeats are also present in other locations in the human genome, including the short arms of all the acrocentric c...
journal_title:Human molecular genetics
pub_type: 杂志文章
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journal_title:Human molecular genetics
pub_type: 杂志文章
doi:10.1093/hmg/3.9.1553
更新日期:1994-09-01 00:00:00
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journal_title:Human molecular genetics
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更新日期:2005-07-15 00:00:00
abstract::Epidermolytic hyperkeratosis (EHK), (bullous congenital ichthyosiform erythroderma), is an autosomal dominant human skin disorder. Recently, we and others have described mutations in keratins 1 and 10 (K1 and K10) in patients with this disease. Structure-function models predict that these mutations would impair normal...
journal_title:Human molecular genetics
pub_type: 杂志文章
doi:10.1093/hmg/2.12.2147
更新日期:1993-12-01 00:00:00
abstract::Defects in FAM161A, a protein of unknown function localized at the cilium of retinal photoreceptor cells, cause retinitis pigmentosa, a form of hereditary blindness. By using different fragments of this protein as baits to screen cDNA libraries of human and bovine retinas, we defined a yeast two-hybrid-based FAM161A i...
journal_title:Human molecular genetics
pub_type: 杂志文章
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更新日期:2015-06-15 00:00:00
abstract::Lysosomal neuraminidase is the key enzyme for the intralysosomal catabolism of sialylated glycoconjugates and is deficient in two neurodegenerative lysosomal disorders, sialidosis and galactosialidosis. Here we report the identification of eight novel mutations in the neuraminidase gene of 11 sialidosis patients with ...
journal_title:Human molecular genetics
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更新日期:2000-11-01 00:00:00
abstract::Haploinsufficiency of the single-minded homology 1 (SIM1) gene in humans and mice leads to severe obesity, suggesting that altered expression of SIM1, by way of regulatory elements such as enhancers, could predispose individuals to obesity. Here, we identified transcriptional enhancers that could regulate SIM1, using ...
journal_title:Human molecular genetics
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更新日期:2014-04-01 00:00:00
abstract::LKB1 is a serine/threonine kinase which is inactivated by mutation in the Peutz-Jeghers polyposis and cancer predisposition syndrome (PJS). We have identified a novel leucine-rich repeat containing protein, LIP1, that interacts with LKB1. The LIP1 gene consists of 25 exons, maps to human chromosome 2q36 and encodes a ...
journal_title:Human molecular genetics
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abstract::XX males and XY females have a sex reversal disorder which can be caused by an abnormal interchange between the X and the Y chromosomes. We have isolated and characterized a novel gene on the Y chromosome, PRKY. This gene is highly homologous to a previously isolated gene from Xp22.3, PRKX, and represents a member of ...
journal_title:Human molecular genetics
pub_type: 杂志文章
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更新日期:1997-10-01 00:00:00
abstract::Microsatellite instability (MSI) characterizes tumors arising in patients with hereditary non-polyposis colorectal cancer (HNPCC) syndrome. HNPCC is a hereditary autosomal dominant disease caused by germline mutations in genes from the DNA (MMR) mismatch repair system. In these tumors, the loss of MMR compromises the ...
journal_title:Human molecular genetics
pub_type: 杂志文章
doi:10.1093/hmg/ddi021
更新日期:2005-01-15 00:00:00