Alteration of protein folding and degradation in motor neuron diseases: Implications and protective functions of small heat shock proteins

Carra, Serena; Crippa, V.; Rusmini, P.; Boncoraglio, Alessandra; Minoia, Melania; Giorgetti, E.; Kampinga, Harm H.; Poletti, Angelo

doi:10.1016/j.pneurobio.2011.09.009

Cited by 68 publications

(73 citation statements)

References 234 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The human family of small HSPs consists of ten members (HSPB1 to HSPB10) 29 , which share a highly conserved C terminal α crystallin domain 80 . Knowledge about the different functionalities of these ten members of the HSPB fam ily is only beginning to emerge, but data indicate their importance in human pathology as a cause of disease when mutated 30,81 . Several small HSPs, including HSPB1, HSPB5, HSPB6, HSPB7, and HSPB8, are abundantly expressed in the human heart and act to conserve sarco meric and structural proteins 82 .…”

Section: Derailment Owing To Genetic Mutationsmentioning

confidence: 99%

Proteostasis in cardiac health and disease

Henning

Brundel²

2017

Nat Rev Cardiol

136

126

View full text Add to dashboard Cite

The worldwide increase in life expectancy gives rise to an increasing prevalence of cardiac diseases, which remain the leading cause of disability and death in the developed world [1][2][3] . Currently, the mechanisms under lying how ageing contributes to the initiation or acceler ation of cardiac diseases are essentially unresolved. Prevailing theories of ageing centre on gradual derail ment of cellular protein homeostasis -proteostasis -either by design (genetically) or by 'wear and tear' (environmentally) 3 . Central to the role of proteostasis derailment as a major factor in ageing is the observation that protein function declines over time.Proteins are the most versatile and complex macro molecules and are involved in the proper functioning of every biological process 4 . After synthesis as a poly peptide chain from the genetic code, proper function of a protein relies heavily on its correct folding into a 3D native state and on various post translational modifi cations, mostly involving the addition of chem ical groups (including phosphate, acetate, and carbo hydrate). Protein maturation, transport, and ultimately breakdown is monitored and supported by various classes of proteins, collectively called 'protein quality control' (PQC) [3][4][5] . Balanced proteostasis, therefore, depends on proper PQC and is crucial for cellular and organismal health 6 . The intricate network making up the PQC involves numerous proteins, of which the main players are the chaperones and their regula tors 4,7-9 (assisting in folding and refolding of proteins) and the pathways that clear irreversibly misfolded and aggregation prone proteins (the ubiquitin-proteasome system [UPS] and autophagy systems) 9-11 . With ageing, the gradual accumulation of misfolded or damaged pro teins, together with concomitant failure of PQC, results in proteotoxic stress and compromised defence against reactive oxygen species (ROS) 10 , a process that is likely to be accelerated in various age related diseases includ ing neurodegenerative diseases 12,13 , type 2 diabetes mel litus 14 , cancer 15 , and cardiac diseases [16][17][18][19][20] . In addition to the accumulation of misfolded proteins, ageing is accompanied by an imbalance in the proteome, as indi cated by lowered expression of chaperone, proteaso mal, ribosomal, and mitochondrial proteins, whereas proteins related to oxidative stress are upregulated 21,22 . Although mild impairment of proteostasis extends lifespan in Caenorhabditis elegans, referred to as hormesis, sustained impairment is accompanied by loss of PQC to neutralize this effect 3,5 . Importantly, evidence indicates that the amount of soluble, aggregate prone protein oligomers, rather than the abundance of pro tein aggregates, correlates with disease severity 23,24 . Therefore, protein aggregates, which contain both misfolded proteins and elevated levels of chaper ones, constitute an adequate PQC response, aimed at sequestering potentially harmful protein oligomers, rather than embodying the ultimate cellular threat 25 . This ...

show abstract

Section: Derailment Owing To Genetic Mutationsmentioning

confidence: 99%

Proteostasis in cardiac health and disease

Henning

Brundel²

2017

Nat Rev Cardiol

136

126

View full text Add to dashboard Cite

show abstract

“…These extensions mediate substrate recognition as well as enabling the formation of oligomers. Small Hsps are able to bind to unfolded or misfolded protein and prevent their aggregation until the protein can be transferred to other cellular systems, such as the Hsp70-Hsp40 system [10].…”

Section: Small Hsp (Hspb) Familymentioning

confidence: 99%

Molecular chaperones and neuronal proteostasis

Smith¹,

Li²,

Cheetham³

2015

Seminars in Cell & Developmental Biology

View full text Add to dashboard Cite

Protein homeostasis (proteostasis) is essential for maintaining the functionality of the proteome. The disruption of proteostasis, due to genetic mutations or an age-related decline, leads to aberrantly folded proteins that typically lose their function. The accumulation of misfolded and aggregated protein is also cytotoxic and has been implicated in the pathogenesis of neurodegenerative diseases. Neurons have developed an intrinsic protein quality control network, of which molecular chaperones are an essential component. Molecular chaperones function to promote efficient folding and target misfolded proteins for refolding or degradation. Increasing molecular chaperone expression can suppress protein aggregation and toxicity in numerous models of neurodegenerative disease; therefore, molecular chaperones are considered exciting therapeutic targets. Furthermore, mutations in several chaperones cause inherited neurodegenerative diseases. In this review, we focus on the importance of molecular chaperones in neurodegenerative diseases, and discuss the advances in understanding their protective mechanisms.

show abstract

“…In vitro, HSPB8 displays chaperone activity (Carra, 2009,Carra, et al, 2012,Carra, et al, 2013,Carra, et al, 2008a,Carra, et al, 2008b. In cells, HSPB8 forms a complex with BAG3, a co-chaperone of HSP70, and promotes the degradation of misfolded proteins resistant to HSPs-dependent refolding ( Figure 1).…”

Section: A) the Chaperonesmentioning

confidence: 99%

“…In cells, HSPB8 forms a complex with BAG3, a co-chaperone of HSP70, and promotes the degradation of misfolded proteins resistant to HSPs-dependent refolding ( Figure 1). Degradation of the bound substrate (ARpolyQ and several other disease-associated misfolded proteins) occurs via autophagy rather than via the UPS and in different cell types, including motor neurons, HeLa cells, COS cells and HEK293T cells (Carra, et al, 2012,Crippa, et al, 2010b,Gamerdinger, et al, 2011.…”

Section: A) the Chaperonesmentioning

confidence: 99%

“…If the proteasome is responsible for wt and ARpolyQ degradation in basal conditions, and autophagy takes over only when the UPS is impaired or overwhelmed, the accumulation of ARpolyQ (in particular in nuclear inclusion) may be linked to a defect in the secondary activation of the protective cytoplasmic autophagic pathway, rather than to an initial failure in proteasome function. A delicate equilibrium exists between the UPS and autophagy, which are both essential for the correct functioning of the PQC system (Carra, et al, 2012,Carra, et al, 2013,Rusmini, et al, 2010. The ARpolyQ re-routing from the proteasome to autophagy may be of relevance for its clearance and it 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64requires specific chaperones that are able to sense proteasome inhibition, such as HSPB8 (Crippa, et al, 2010a,Crippa, et al, 2010b and the co-chaperones BAG3 (for autophagic clearance) and BAG1 (for UPS clearance) ( Figure 1) (Gamerdinger, et al, 2011).…”

Section: C) Autophagymentioning

confidence: 99%

See 1 more Smart Citation

The Role of the Protein Quality Control System in SBMA

et al. 2015

Self Cite

View full text Add to dashboard Cite

Spinal and Bulbar Muscular Atrophy (SBMA) or Kennedy's disease is an X-linked disease associated with the expansion of the CAG triplet repeat present in exon-1 on the androgen receptor (AR) gene. This results in the production of a mutant AR containing an elongated polyglutamine tract (polyQ) in its N-terminus. Interestingly, the ARpolyQ becomes toxic only after its activation by the natural androgenic ligands, possibly because of aberrant androgen-induced conformational changes of the ARpolyQ, which generate misfolded species. These misfolded ARpolyQ species must be cleared from motoneurons and muscle cells, and this process is mediated by the protein quality control (PQC) system. Experimental evidence suggested that failure of the PQC pathways occurs in disease, leading to ARpolyQ accumulation and toxicity in the target cells. In these review we summarized the overall impact of mutant and misfolded ARpolyQ on the PQC system and described how molecular chaperons and the degradative pathways (ubiquitin-proteasome system (UPS), the autophagy-lysosome pathway (ALP), and the unfolded protein response (UPR), which activates the endoplasmic reticulum-associated degradation (ERAD)) are differentially affected in SBMA. We also extensively and critically reviewed several molecular and pharmacological approaches proposed to restore a global intracellular activity of the PQC system. Collectively, these data suggest that the fine and delicate equilibrium existing among the different players of the PQC system could be restored in a therapeutic perspective by the synergic/additive activities of compounds designed to tackle sequential or alternative steps of the intracellular defense mechanisms triggered against proteotoxic misfolded species.

show abstract

Alteration of protein folding and degradation in motor neuron diseases: Implications and protective functions of small heat shock proteins

Cited by 68 publications

References 234 publications

Proteostasis in cardiac health and disease

Proteostasis in cardiac health and disease

Molecular chaperones and neuronal proteostasis

The Role of the Protein Quality Control System in SBMA

Contact Info

Product

Resources

About