Folding or holding?—Hsp70 and Hsp90 chaperoning of misfolded proteins in neurodegenerative disease

Rutledge, Benjamin S.; Choy, Wing‐Yiu; Duennwald, Martin L.

doi:10.1016/j.jbc.2022.101905

Cited by 52 publications

(28 citation statements)

References 79 publications

(157 reference statements)

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“…HSP70 has been previously described as being included in PABPN1 nuclear aggregates, possibly through sequestration [ 62 ]. HSP70 is a molecular chaperone involved in both the refolding and handling of misfolded proteins [ 54 ] and is commonly associated with protein aggregates [ 29 ]. HSP70 binds in vitro to mutated PABPN1 with a higher affinity than to wild-type PABPN1 and it has been shown that the binding efficiency is proportional to the length of the PABPN1 expansion [ 62 ].…”

Section: Discussionmentioning

confidence: 99%

Assessment of PABPN1 nuclear inclusions on a large cohort of patients and in a human xenograft model of oculopharyngeal muscular dystrophy

et al. 2022

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Oculopharyngeal muscular dystrophy (OPMD) is a rare muscle disease characterized by an onset of weakness in the pharyngeal and eyelid muscles. The disease is caused by the extension of a polyalanine tract in the Poly(A) Binding Protein Nuclear 1 (PABPN1) protein leading to the formation of intranuclear inclusions or aggregates in the muscle of OPMD patients. Despite numerous studies stressing the deleterious role of nuclear inclusions in cellular and animal OPMD models, their exact contribution to human disease is still unclear. In this study, we used a large and unique collection of human muscle biopsy samples to perform an in-depth analysis of PABPN1 aggregates in relation to age, genotype and muscle status with the final aim to improve our understanding of OPMD physiopathology. Here we demonstrate that age and genotype influence PABPN1 aggregates: the percentage of myonuclei containing PABPN1 aggregates increases with age and the chaperone HSP70 co-localize more frequently with PABPN1 aggregates with a larger polyalanine tract. In addition to the previously described PRMT1 and HSP70 co-factors, we identified new components of PABPN1 aggregates including GRP78/BiP, RPL24 and p62. We also observed that myonuclei containing aggregates are larger than myonuclei without. When comparing two muscles from the same patient, a similar amount of aggregates is observed in different muscles, except for the pharyngeal muscle where fewer aggregates are observed. This could be due to the peculiar nature of this muscle which has a low level of PAPBN1 and contains regenerating fibers. To confirm the fate of PABPN1 aggregates in a regenerating muscle, we generated a xenograft model by transplanting human OPMD muscle biopsy samples into the hindlimb of an immunodeficient mouse. Xenografts from subjects with OPMD displayed regeneration of human myofibers and PABPN1 aggregates were rapidly present—although to a lower extent-after muscle fiber regeneration. Our data obtained on human OPMD samples add support to the dual non-exclusive models in OPMD combining toxic PABPN1 intranuclear inclusions together with PABPN1 loss of function which altogether result in this late-onset and muscle selective disease.

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Section: Discussionmentioning

confidence: 99%

Assessment of PABPN1 nuclear inclusions on a large cohort of patients and in a human xenograft model of oculopharyngeal muscular dystrophy

et al. 2022

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“…In many reports, the level of HSP70 changes in biofluids along with the severity of several diseases. Changes in the level of HSP70 can be used to diagnose/prognosis in some other diseases, such as diabetes [ 14 , 50 ], cancer [ 13 , 51 ], heart diseases [ 52 , 53 ], and neurodegenerative disease [ 54 , 55 ]. Fig.…”

Section: Resultsmentioning

confidence: 99%

Sandwich-like electrochemical aptasensing of heat shock protein 70 kDa (HSP70): Application in diagnosis/prognosis of coronavirus disease 2019 (COVID-19)

Negahdary

Hirata

Sakata

et al. 2023

Analytica Chimica Acta

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“…4A, E ). Similar to HSP70, HSP90 chaperones bind to misfolded proteins, including TDP-43, and assist in their transition to native conformation or prevent their accumulation in misfolded state ( 57 ). Of particular interest is the 1.8-fold increase in expression of CLU in upper layer excitatory neurons ( Fig.…”

Section: Resultsmentioning

confidence: 99%

Divergent impacts ofC9orf72repeat expansion on neurons and glia in ALS and FTD

Jaiswal

Chien

et al. 2022

Preprint

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Neurodegenerative diseases, such as amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), are strongly influenced by inherited genetic variation, but environmental and epigenetic factors also play key roles in the course of these diseases. A hexanucleotide repeat expansion in the C9orf72 (C9) gene is the most common genetic cause of ALS and FTD. To determine the cellular alterations associated with the C9 repeat expansion, we performed single nucleus transcriptomics (snRNA-seq) and epigenomics (snATAC-seq) in postmortem samples of motor and frontal cortices from C9-ALS and C9-FTD donors. We found pervasive alterations of gene expression across multiple cortical cell types in C9-ALS, with the largest number of affected genes in astrocytes and excitatory neurons. Astrocytes increased expression of markers of activation and pathways associated with structural remodeling. Excitatory neurons in upper and deep layers increased expression of genes related to proteostasis, metabolism, and protein expression, and decreased expression of genes related to neuronal function. Epigenetic analyses revealed concordant changes in chromatin accessibility, histone modifications, and gene expression in specific cell types. C9-FTD patients had a distinct pattern of changes, including loss of neurons in frontal cortex and altered expression of thousands of genes in astrocytes and oligodendrocyte-lineage cells. Overall, these findings demonstrate a context-dependent molecular disruption in C9-ALS and C9-FTD, resulting in distinct effects across cell types, brain regions, and disease phenotypes.

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Folding or holding?—Hsp70 and Hsp90 chaperoning of misfolded proteins in neurodegenerative disease

Cited by 52 publications

References 79 publications

Assessment of PABPN1 nuclear inclusions on a large cohort of patients and in a human xenograft model of oculopharyngeal muscular dystrophy

Assessment of PABPN1 nuclear inclusions on a large cohort of patients and in a human xenograft model of oculopharyngeal muscular dystrophy

Sandwich-like electrochemical aptasensing of heat shock protein 70 kDa (HSP70): Application in diagnosis/prognosis of coronavirus disease 2019 (COVID-19)

Divergent impacts ofC9orf72repeat expansion on neurons and glia in ALS and FTD

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