The Role of the Protein Quality Control System in SBMA

Rusmini, P.; Crippa, V.; Cristofani, R.; Rinaldi, Carlo; Cicardi, M.E.; Galbiati, M.; Carra, Serena; Malik, Bilal; Greensmith, Linda; Poletti, Angelo

doi:10.1007/s12031-015-0675-6

Cited by 32 publications

(34 citation statements)

References 159 publications

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“…The UPS could be overwhelmed by an excess of misfolded proteins or clogged by the polyQ (Ciechanover and Kwon, 2015; Rusmini et al, 2016); the autophagic flux could be blocked by misfolded protein aggregates (Rusmini et al, 2013). However, the molecular steps altered by misfolded proteins in these pathways are poorly understood.…”

Section: Als and Sbma As Models To Study Misfolded Proteins In Mndsmentioning

confidence: 99%

The Role of the Heat Shock Protein B8 (HSPB8) in Motoneuron Diseases

Rusmini

Cristofani

Galbiati

et al. 2017

Front. Mol. Neurosci.

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Amyotrophic lateral sclerosis (ALS) and spinal and bulbar muscular atrophy (SBMA) are two motoneuron diseases (MNDs) characterized by aberrant protein behavior in affected cells. In familial ALS (fALS) and in SBMA specific gene mutations lead to the production of neurotoxic proteins or peptides prone to misfold, which then accumulate in form of aggregates. Notably, some of these proteins accumulate into aggregates also in sporadic ALS (sALS) even if not mutated. To prevent proteotoxic stresses detrimental to cells, misfolded and/or aggregated proteins must be rapidly removed by the protein quality control (PQC) system. The small heat shock protein B8 (HSPB8) is a chaperone induced by harmful events, like proteasome inhibition. HSPB8 is expressed both in motoneuron and muscle cells, which are both targets of misfolded protein toxicity in MNDs. In ALS mice models, in presence of the mutant proteins, HSPB8 is upregulated both in spinal cord and muscle. HSPB8 interacts with the HSP70 co-chaperone BAG3 and enhances the degradation of misfolded proteins linked to sALS, or causative of fALS and of SBMA. HSPB8 acts by facilitating autophagy, thereby preventing misfolded protein accumulation in affected cells. BAG3 and BAG1 compete for HSP70-bound clients and target them for disposal to the autophagy or proteasome, respectively. Enhancing the selective targeting of misfolded proteins by HSPB8-BAG3-HSP70 to autophagy may also decrease their delivery to the proteasome by the BAG1-HSP70 complex, thereby limiting possible proteasome overwhelming. Thus, approaches aimed at potentiating HSPB8-BAG3 may contribute to the maintenance of proteostasis and may delay MNDs progression.

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Section: Als and Sbma As Models To Study Misfolded Proteins In Mndsmentioning

confidence: 99%

The Role of the Heat Shock Protein B8 (HSPB8) in Motoneuron Diseases

Rusmini

Cristofani

Galbiati

et al. 2017

Front. Mol. Neurosci.

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“…These enzymes serve a key role in targeting proteins for degradation both by the proteasome and autophagy (Pratt et al, 2015; Rusmini et al, 2016). In the last decade, a great deal of focus has been placed on C-terminal Hsp70-interacting protein (CHIP), which acts as both a co-chaperone and an E3 ubiquitin ligase for misfolded proteins and plays a key role in facilitating their degradation (Pratt et al, 2015).…”

Section: Ubiquitinating Enzymes (E3s) In Polyq Diseasesmentioning

confidence: 99%

“…This review will focus on pathways involved in mutant protein degradation, highlighting pathophysiologic changes, and possible therapeutic targets within the fields of ubiquitination, deubiquitinating enzymes, protein disaggregation, and proteasomal activity. Though misfolded proteins are also degraded through autophagy, several excellent recent reviews have detailed the contribution of this pathway to their clearance and potential strategies for therapeutic manipulation (Martin et al, 2015; Rusmini et al, 2015, 2016). …”

Section: Introductionmentioning

confidence: 99%

The Ubiquitination, Disaggregation and Proteasomal Degradation Machineries in Polyglutamine Disease

Nath

Lieberman

2017

Front. Mol. Neurosci.

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Polyglutamine disorders are chronic, progressive neurodegenerative diseases caused by expansion of a glutamine tract in widely expressed genes. Despite excellent models of disease, a well-documented clinical history and progression, and established genetic causes, there are no FDA approved, disease modifying treatments for these disorders. Downstream of the mutant protein, several divergent pathways of toxicity have been identified over the last several decades, supporting the idea that targeting only one of these pathways of toxicity is unlikely to robustly alleviate disease progression. As a result, a vast body of research has focused on eliminating the mutant protein to broadly prevent downstream toxicity, either by silencing mutant protein expression or leveraging the endogenous protein quality control machinery. In the latter approach, a focus has been placed on four critical components of mutant protein degradation that are active in the nucleus, a key site of toxicity: disaggregation, ubiquitination, deubiquitination, and proteasomal activity. These machineries have unique functional components, but work together as a cellular defense system that can be successfully leveraged to alleviate disease phenotypes in several models of polyglutamine toxicity. This review will highlight recent advances in understanding both the potential and role of these components of the protein quality control machinery in polyglutamine disease pathophysiology.

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“…Angelo Poletti, Paola Rusmini, Carlo Rinaldi, Linda Greensmith, and colleagues present the review entitled "The role of the protein quality control system in SBMA" (Rusmini et al 2015). Here, the authors describe the role of the protein quality control system in the pathogenesis of SBMA.…”

Section: Introductionmentioning

confidence: 99%

Introduction to the Special Issue on Spinal and Bulbar Muscular Atrophy

Pennuto

Gozes

2016

J Mol Neurosci

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This special issue is dedicated to spinal and bulbar muscular atrophy (SBMA) and is based on the conference sponsored by the European Neuromuscular Centre (ENMC) held in March 2015. SBMA, also known as Kennedy's disease, is a neurodegenerative disease caused by an expansion of a repeat of the trinucleotide CAG encoding glutamine in the gene encoding androgen receptor (AR). Expansion of polyglutamine in the AR results in selective lower motor neuron degeneration and skeletal muscle atrophy. SBMA belongs to the family of polyglutamine diseases, which also inc l u d e s H u n t i n g t o n 's d i s e a s e , d e n t a t o r u b r a lpallidoluysian atrophy, and spinocerebellar ataxia m a l e s a r e u s u a l l y a s y m p t o m a t i c . I n d e e d , t h e polyglutamine-expanded AR is converted to a neurotoxic species upon binding to androgens. The mechanisms through which androgen binding triggers the disease are under investigation. Although several therapeutic strategies have been proposed to date, there is currently no effective therapy to arrest or delay disease progression in patients.

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The Role of the Protein Quality Control System in SBMA

Cited by 32 publications

References 159 publications

The Role of the Heat Shock Protein B8 (HSPB8) in Motoneuron Diseases

The Role of the Heat Shock Protein B8 (HSPB8) in Motoneuron Diseases

The Ubiquitination, Disaggregation and Proteasomal Degradation Machineries in Polyglutamine Disease

Introduction to the Special Issue on Spinal and Bulbar Muscular Atrophy

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