A role of small heat shock protein B8 (HspB8) in the autophagic removal of misfolded proteins responsible for neurodegenerative diseases

Crippa, V.; Carra, Serena; Rusmini, P.; Sau, D.; Bolzoni, Elena; Bendotti, Caterina; Biasi, S. De; Poletti, Angelo

doi:10.4161/auto.6.7.13042

Cited by 99 publications

(100 citation statements)

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“…Among these HSPB members, HSPB8 is probably the most studied in this context. Overexpression of HSPB8 efficiently prevents aggregation of different polyQ-containing proteins (huntingtin, ataxin-3 and androgen receptor (AR), responsible for HD, spinocerebellar ataxia type 3 (SCA3) and SBMA, respectively) [1,47,101], as well as SOD1 ( protein responsible for ALS) and various truncated forms of TDP-43s (associated with both ALS and frontotemporal dementia (FTD; table 1)) [43,95]. Figure 2 illustrates this for the mutant ARpolyQ that causes SBMA.…”

Section: Refolding and Anti-aggregation Are Distinct Properties Of Thmentioning

confidence: 99%

Different anti-aggregation and pro-degradative functions of the members of the mammalian sHSP family in neurological disorders

Carra

Rusmini

Crippa

et al. 2013

Phil. Trans. R. Soc. B

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The family of the mammalian small heat-shock proteins consists of 10 members (sHSPs/HSPBs: HSPB1–HSPB10) that all share a highly conserved C-terminal alpha-crystallin domain, important for the modulation of both their structural and functional properties. HSPB proteins are biochemically classified as molecular chaperones and participate in protein quality control, preventing the aggregation of unfolded or misfolded proteins and/or assisting in their degradation. Thus, several members of the HSPB family have been suggested to be protective in a number of neurodegenerative and neuromuscular diseases that are characterized by protein misfolding. However, the pro-refolding, anti-aggregation or pro-degradative properties of the various members of the HSPB family differ largely, thereby influencing their efficacy and protective functions. Such diversity depends on several factors, including biochemical and physical properties of the unfolded/misfolded client, the expression levels and the subcellular localization of both the chaperone and the client proteins. Furthermore, although some HSPB members are inefficient at inhibiting protein aggregation, they can still exert neuroprotective effects by other, as yet unidentified, manners; e.g. by maintaining the proper cellular redox state or/and by preventing the activation of the apoptotic cascade. Here, we will focus our attention on how the differences in the activities of the HSPB proteins can influence neurodegenerative and neuromuscular disorders characterized by accumulation of aggregate-prone proteins. Understanding their mechanism of action may allow us to target a specific member in a specific cell type/disease for therapeutic purposes.

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Section: Refolding and Anti-aggregation Are Distinct Properties Of Thmentioning

confidence: 99%

Different anti-aggregation and pro-degradative functions of the members of the mammalian sHSP family in neurological disorders

Carra

Rusmini

Crippa

et al. 2013

Phil. Trans. R. Soc. B

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“…The positive effect of upregulating autophagy in ALS has been pointed out in SOD1 models (Hetz et al, 2009;Crippa et al, 2010a). Small heat shock protein HspB8 decreases the aggregation and promotes the clearance of mutant SOD1 in SOD1 G93A mice, with no impact on the turnover of the wild-type protein (Crippa et al, 2010a).…”

Section: Accumulation Of Als Pathogenetic Proteins and Autophagymentioning

confidence: 99%

“…Aggregates in turn might cause UPS dysfunction (Crippa et al, 2010a) and compensatory induction of autophagy (Korolchuk et al, 2010). In spinal MNs from animal models of ALS (Li et al, 2008) and in post-mortem samples of ALS cases (Sasaki, 2011) the alteration of UPS and activation of autophagy have been observed (Li et al, 2008;Sasaki, 2011).…”

Section: Accumulation Of Als Pathogenetic Proteins and Autophagymentioning

confidence: 99%

“…Small heat shock protein HspB8 decreases the aggregation and promotes the clearance of mutant SOD1 in SOD1 G93A mice, with no impact on the turnover of the wild-type protein (Crippa et al, 2010a). The enhancement of macroautophagy, observed in X-box-binding protein-1 (XBP-1) knockout mice, where the pathway known as unfolded protein response is impaired, led to an increased clearance of mutant SOD1 aggregates in spinal cord (Hetz et al, 2009).…”

Section: Accumulation Of Als Pathogenetic Proteins and Autophagymentioning

confidence: 99%

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Autophagy in motor neuron disease: Key pathogenetic mechanisms and therapeutic targets

Mis

Brajkovic

Frattini

et al. 2016

Molecular and Cellular Neuroscience

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a b s t r a c tAutophagy is a lysosome-dependant intracellular degradation process that eliminates long-lived proteins as well as damaged organelles from the cytoplasm. An increasing body of evidence suggests that dysregulation of this system plays a pivotal role in the etiology and/or progression of neurodegenerative diseases including motor neuron disorders. Herein, we review the latest findings that highlight the involvement of autophagy in the pathogenesis of amyotrophic lateral sclerosis (ALS) and the potential role of this pathway as a target of therapeutic purposes. Autophagy promotes the removal of toxic, cytoplasmic aggregate-prone pathogenetic proteins, enhances cell survival, and modulates inflammation. The existence of several drugs targeting this pathway can facilitate the translation of basic research to clinical trials for ALS and other motor neuron diseases..

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“…Together with the chaperone-associated ubiquitin ligase CHIP, this complex functions to remove misfolded proteins. It enables the ubiquitylation of the mutant superoxide dismutase (mSOD1) protein that is implicated in the development of amyotrophic lateral sclerosis (ALS), promoting its autophagic removal (Crippa et al, 2010a;Crippa et al, 2010b;Rosati et al, 2011;Vos et al, 2011). HspB8/Bag-3 interaction also has an important role in the protection of astrocytes against different protein aggregation diseases, apparently through autophagy-related aggregate clearance (Seidel et al, 2012) and it may contribute to chaperone-assisted selective autophagy in limbgirdle muscular dystrophy type 1D (LGMD1D), a myopathy caused by mutations of the Hsp40 family member DNAJB6 (Sato et al, 2013).…”

Section: Inhibition Of Unfolded Protein Response (Upr)mentioning

confidence: 99%

HSPB8 (heat shock 22kDa protein 8)

Bollino¹,

Aurelian²

2014

Atlas of Genetics and Cytogenetics in Oncology and Haematology

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A role of small heat shock protein B8 (HspB8) in the autophagic removal of misfolded proteins responsible for neurodegenerative diseases

Abstract: (2010) A role of small heat shock protein B8 (HspB8) in the autophagic removal of misfolded proteins responsible for neurodegenerative diseases, Autophagy, 6:7,[958][959][960]

Cited by 99 publications

References 1 publication

Different anti-aggregation and pro-degradative functions of the members of the mammalian sHSP family in neurological disorders

Different anti-aggregation and pro-degradative functions of the members of the mammalian sHSP family in neurological disorders

Autophagy in motor neuron disease: Key pathogenetic mechanisms and therapeutic targets

HSPB8 (heat shock 22kDa protein 8)

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