Protein homeostasis and aging in neurodegeneration

Douglas, Peter M.; Dillin, Andrew

doi:10.1084/jem20710oia26

Cited by 69 publications

(102 citation statements)

References 104 publications

(114 reference statements)

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“…In general, cytotoxicity of Aβ is considered to depend on its initial assembly into detrimental oligomers. In contrast to Aβ monomers, which in other systems are considered not cytotoxic (recently reviewed in [61,62]), small oligomers and protofibrils are thought to be the cytotoxic forms of Aβ42 [46,61,62,67]. In s-IBM muscle biopsies, Aβ42-dimers, -trimers and -tetramers were evident by immunoblots [66], thereby providing additional evidence that intra-muscle-fiber accumulation of Aβ42 oligomers may contribute importantly to the s-IBM pathogenic cascade.…”

Section: Accumulation Of Aβ42 and Evidence Of Putatively Toxic Aβ42 Omentioning

confidence: 95%

“…The term "proteostasis" describes the integrated cellular network that controls the life of proteins from their initiation to termination [46,47]. Proteostasis is considered a broader term than "protein qualitycontrol" because it encompasses regulation of protein transcription, translation, folding, processing, assembly/disassembly and degradation [46,47].…”

Section: Abnormal Myoproteostasismentioning

confidence: 99%

“…Proteostasis is considered a broader term than "protein qualitycontrol" because it encompasses regulation of protein transcription, translation, folding, processing, assembly/disassembly and degradation [46,47]. Although some abnormal aspects of proteostasis are present in every abnormal cell, abnormal proteostasis is considered especially important in several neurodegenerative diseases of brain [46] and in s-IBM muscle fibers, where accumulated protein aggregates contain various proteins in different stages of abnormal proteostasis [25].…”

Section: Abnormal Myoproteostasismentioning

confidence: 99%

“…Previously for years it had been considered that only extracellular Aβ is detrimental in AD brain [60]. Now, however, the presence of intraneuronal Aβ is well established and its possible toxicity and importance in the AD pathogenesis are being considered (reviewed in [46,61,62].…”

Section: Accumulation Of Aβ42 and Evidence Of Putatively Toxic Aβ42 Omentioning

confidence: 99%

“…This control or surveillance machinery is particularly important for the non-dividing post-mitotic cells like neurons or muscle fibers, because their accumulated abnormal proteins cannot be diluted during cell division [91]. Under various pathological conditions and in aging, protein quality-control is disturbed (reviewed in [46,91,95]). …”

Section: Abnormal Protein Disposalmentioning

confidence: 99%

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Sporadic inclusion-body myositis: A degenerative muscle disease associated with aging, impaired muscle protein homeostasis and abnormal mitophagy

Askanas

Engel

Nogalska

2015

Biochimica et Biophysica Acta (BBA) - Molecular Basis of Diseas

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Sporadic inclusion-body myositis (s-IBM) is the most common degenerative muscle disease in which aging appears to be a key risk factor. In this review we focus on several cellular molecular mechanisms responsible for multiprotein aggregation and accumulations within s-IBM muscle fibers, and their possible consequences. Those include mechanisms leading to: a) accumulation in the form of aggregates within the muscle fibers, of several proteins, including amyloid-β42 and its oligomers, and phosphorylated tau in the form of paired helical filaments, and we consider their putative detrimental influence; and b) protein misfolding and aggregation, including evidence of abnormal myoproteostasis, such as increased protein transcription, inadequate protein disposal, and abnormal posttranslational modifications of proteins. Pathogenic importance of our recently demonstrated abnormal mitophagy is also discussed. The intriguing phenotypic similarities between s-IBM muscle fibers and the brains of Alzheimer and Parkinson's disease patients, the two most common neurodegenerative diseases associated with aging, are also discussed. This article is part of a Special Issue entitled: Neuromuscular Diseases: Pathology and Molecular Pathogenesis.

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Section: Accumulation Of Aβ42 and Evidence Of Putatively Toxic Aβ42 Omentioning

confidence: 95%

Section: Abnormal Myoproteostasismentioning

confidence: 99%

Section: Abnormal Myoproteostasismentioning

confidence: 99%

Section: Accumulation Of Aβ42 and Evidence Of Putatively Toxic Aβ42 Omentioning

confidence: 99%

Section: Abnormal Protein Disposalmentioning

confidence: 99%

See 3 more Smart Citations

Sporadic inclusion-body myositis: A degenerative muscle disease associated with aging, impaired muscle protein homeostasis and abnormal mitophagy

Askanas

Engel

Nogalska

2015

Biochimica et Biophysica Acta (BBA) - Molecular Basis of Diseas

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Repair or destruction—an intimate liaison between ubiquitin ligases and molecular chaperones in proteostasis

2017

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Cellular differentiation, developmental processes, and environmental factors challenge the integrity of the proteome in every eukaryotic cell. The maintenance of protein homeostasis, or proteostasis, involves folding and degradation of damaged proteins, and is essential for cellular function, organismal growth, and viability 1, 2. Misfolded proteins that cannot be refolded by chaperone machineries are degraded by specialized proteolytic systems. A major degradation pathway regulating cellular proteostasis is the ubiquitin (Ub)/proteasome system (UPS), which regulates turnover of damaged proteins that accumulate upon stress and during aging. Despite a large number of structurally unrelated substrates, Ub conjugation is remarkably selective. Substrate selectivity is mainly provided by the group of E3 enzymes. Several observations indicate that numerous E3 Ub ligases intimately collaborate with molecular chaperones to maintain the cellular proteome. In this review, we provide an overview of specialized quality control E3 ligases playing a critical role in the degradation of damaged proteins. The process of substrate recognition and turnover, the type of chaperones they team up with, and the potential pathogeneses associated with their malfunction will be further discussed.

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Stability in BMI over time is associated with a better cognitive trajectory in older adults

Beeri

Tirosh

Lin

et al. 2022

Alzheimer's & Dementia

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Objective Evidence on simultaneous changes in body mass index (BMI) and cognitive decline, which better reflect the natural course of both health phenomena, is limited. Methods We capitalized on longitudinal data from 15,977 initially non‐demented elderly from the Alzheimer's Disease Centers followed for 5 years on average. Changes in BMI were defined as (1) last minus first BMI, (2) mean of all follow‐up BMIs minus first BMI, and (3) standard deviation of BMI change from baseline and all follow‐up visits (representing variability). Results Participants with significant changes in BMI (increase or decrease of ≥5%), or who had greater variability in BMI, had faster cognitive decline. This pattern was consistent irrespective of normal (BMI < 25; N = 5747), overweight (25 ≤ BMI < 30; N = 6302), or obese (BMI ≥ 30; N = 3928) BMI at baseline. Conclusions Stability in BMI predicts better cognitive trajectories suggesting clinical value in tracking BMI change, which is simple to measure, and may point to individuals whose cognition is declining.

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Protein homeostasis and aging in neurodegeneration

Cited by 69 publications

References 104 publications

Sporadic inclusion-body myositis: A degenerative muscle disease associated with aging, impaired muscle protein homeostasis and abnormal mitophagy

Sporadic inclusion-body myositis: A degenerative muscle disease associated with aging, impaired muscle protein homeostasis and abnormal mitophagy

Repair or destruction—an intimate liaison between ubiquitin ligases and molecular chaperones in proteostasis

Stability in BMI over time is associated with a better cognitive trajectory in older adults

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