Endoplasmic reticulum stress: The cause and solution to Huntington's disease?

Jiang, Yuwei; Chadwick, Sarah R.; Lajoie, Patrick

doi:10.1016/j.brainres.2016.03.034

Cited by 53 publications

(49 citation statements)

References 112 publications

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“…248, 265 For example, exogenous cholesterol protects lipid bilayers from htt induced disruption, 264 which is particularly important provided that HD patients have altered cholesterol homeostasis. 266, 267 Membrane degradation of the nuclear envelope, ER, and mitochondria has been described to the presence of mutant htt, 76, 162 and expanded polyQ can generically distort ER membranes and the nuclear envelope in cell culture. 163 Stabilized oligomers species of htt are associated with mitochondrial structural proteins, and can lead to mitochondrial fragmentation, abnormal mitochondrial dynamics, and oxidative DNA damage.…”

Section: Interaction With Lipids Influence Polyq Aggregation and Locamentioning

confidence: 99%

Proteins Containing Expanded Polyglutamine Tracts and Neurodegenerative Disease

et al. 2017

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Several hereditary neurological and neuromuscular diseases are caused by an abnormal expansion of trinucleotide repeats. To date, there have been ten of these trinucleotide repeat disorders associated with an expansion of the codon CAG encoding glutamine (Q). For these polyglutamine (polyQ) diseases, there is a critical threshold length of the CAG repeat required for disease, and further expansion beyond this threshold is correlated with age of onset and symptom severity. PolyQ expansion in the translated proteins promotes their self-assembly into a variety of oligomeric and fibrillar aggregate species that accumulate into the hallmark proteinaceous inclusion bodies associated with each disease. Here, we review aggregation mechanisms of proteins with expanded polyQ-tracts, structural consequences of expanded polyQ ranging from monomers to fibrillar aggregates, the impact of protein context and post translational modifications on aggregation, and a potential role for lipids membranes in aggregation. As the pathogenic mechanisms that underlie these disorders are often classified as either a gain of toxic function or loss of normal protein function, some toxic mechanisms associated with mutant polyQ tracts will also be discussed.

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Section: Interaction With Lipids Influence Polyq Aggregation and Locamentioning

confidence: 99%

Proteins Containing Expanded Polyglutamine Tracts and Neurodegenerative Disease

et al. 2017

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“…Accordantly, the presence of ER stress markers have been described in patient samples with AD [17,18], PD [19], HD [20], ALS [21], and Prion diseases [22] and ER stress markers often co-localize with protein aggregates in the brain of patients [1,5,[23][24][25]. Those findings could be interpreted as (i) neuroprotective signals to sustain proteostasis, (ii) a pro-degenerative stimuli due to chronic ER dysfunction or (iii) and epiphenomena that is irrelevant to the disease process (Figure 2).…”

Section: Upr Protein Aggregates and Neurodegeneration -A Complex Intmentioning

confidence: 78%

“…HD is caused by a mutation in the first exon of the Huntingtin (HTT) gene, which contains a tract of glutamine residues (polyQ repeats) that can vary in length amongst individuals resulting in a mutated protein HTT with an expanded CAG repeat [20] that are believed to exert a toxic gain of function [127,128]. Accordingly, polyQ expansions in different proteins are directly related to the pathology of at least nine different neurodegenerative disorders, including HD; one of each represented by a different subset of vulnerable neuronal populations [131].…”

Section: Huntington's Diseasementioning

confidence: 99%

“…Accordingly, polyQ expansions in different proteins are directly related to the pathology of at least nine different neurodegenerative disorders, including HD; one of each represented by a different subset of vulnerable neuronal populations [131]. Expression of mutant HTT and aggregate formation in cytosol and nucleus are believed to overcome the proteostasis machinery, thus altering cell normal physiology [20]. Mutant HTT may disrupt different cellular pathways related to protein turnover [132], transport [131] and the UPS [132,130] in addition to induce ER stress in cellular models [9,135,136].…”

Section: Huntington's Diseasementioning

confidence: 99%

“…In contrast, ATF4 deficiency did not affect mutant HTT aggregation [8]. As autophagy is suggested to be the preferential degradation pathway for misfolded protein aggregates, including those formed as part of mutant HTT [20] and is proposed to fail in the disease process [140], XBP1 may stand as a central mediator of HTT clearance in HD pathogenesis. Accordingly, delivering AAV-XBP1 to the striatum of adult mice overexpressing a mutant HTT reduced its accumulation [141].…”

Section: Huntington's Diseasementioning

confidence: 99%

See 2 more Smart Citations

ER stress in neurodegenerative disease: from disease mechanisms to therapeutic interventions

Cabral‐Miranda

Hetz

2017

Endoplasmic Reticulum Stress in Diseases

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The conception that protein aggregates composed by misfolded proteins underlies the occurrence of several neurodegenerative diseases suggests that this phenomenon may have a common origin, ultimately driven by disruption of proteostasis control. The unfolded protein response (UPR) embodies a major element of the proteostasis network, which is engaged by endoplasmic reticulum (ER) stress. Chronic ER stress may operate as a possible mechanism of neurodegeneration, contributing to synaptic alterations, neuroinflammation and neuronal loss. In this review we discuss most recent findings relating ER stress and the development of distinct neurodegenerative diseases, and the possible strategies for disease intervention.

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ER Stress and Neurodegenerative Disease: A Cause or Effect Relationship?

Cabral‐Miranda

Hetz

2017

Current Topics in Microbiology and Immunology

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The accumulation of protein aggregates has a fundamental role in the patophysiology of distinct neurodegenerative diseases. This phenomenon may have a common origin, where disruption of intracellular mechanisms related to protein homeostasis (here termed proteostasis) control during aging may result in abnormal protein aggregation. The unfolded protein response (UPR) embodies a major element of the proteostasis network triggered by endoplasmic reticulum (ER) stress. Chronic ER stress may operate as possible mechanism of neurodegenerative and synaptic dysfunction, and in addition contribute to the abnormal aggregation of key disease-related proteins. In this article we overview the most recent findings suggesting a causal role of ER stress in neurodegenerative diseases.

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Endoplasmic reticulum stress: The cause and solution to Huntington's disease?

Cited by 53 publications

References 112 publications

Proteins Containing Expanded Polyglutamine Tracts and Neurodegenerative Disease

Proteins Containing Expanded Polyglutamine Tracts and Neurodegenerative Disease

ER stress in neurodegenerative disease: from disease mechanisms to therapeutic interventions

ER Stress and Neurodegenerative Disease: A Cause or Effect Relationship?

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