Hsp31 Is a Stress Response Chaperone That Intervenes in the Protein Misfolding Process

Tsai, Chai-jui; Aslam, Kiran; Drendel, Holli M.; Asiago, Josephat M.; Goode, Kourtney M.; Paul, Lake N.; Rochet, Jean‐Christophe; Hazbun, Tony R.

doi:10.1074/jbc.m115.678367

Cited by 38 publications

(67 citation statements)

References 76 publications

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“…This further supports the involvement of this class of paralog heat-shock proteins in suppressing αSyn toxicity. Consistently, HSP31 (which among HSP31–34 shows the least homology with DJ-1 ) was recently shown to be a chaperone involved in mitigating various protein misfolding stresses, including that of αSyn (Tsai et al, 2015). …”

Section: Resultsmentioning

confidence: 81%

Randomized CRISPR-Cas Transcriptional Perturbation Screening Reveals Protective Genes against Alpha-Synuclein Toxicity

et al. 2017

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SUMMARY The genome-wide perturbation of transcriptional networks with CRISPR-Cas technology has primarily involved systematic and targeted gene modulation. Here, we developed PRISM (Perturbing Regulatory Interactions by Synthetic Modulators), a screening platform that uses randomized CRISPR-Cas transcription factors (crisprTFs) to globally perturb transcriptional networks. By applying PRISM to a yeast model of Parkinson’s disease (PD), we identified guide RNAs (gRNAs) that modulate transcriptional networks and protect cells from alpha-synuclein (αSyn) toxicity. One gRNA identified in this screen outperformed the most protective suppressors of αSyn toxicity reported previously, highlighting PRISM’s ability to identify modulators of important phenotypes. Gene expression profiling revealed genes differentially modulated by this strong protective gRNA that rescued yeast from αSyn toxicity when overexpressed. Human homologs of top-ranked hits protected against αSyn-induced cell death in a human neuronal PD model. Thus, high-throughput and unbiased perturbation of transcriptional networks via randomized crisprTFs can reveal complex biological phenotypes and effective disease modulators.

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Section: Resultsmentioning

confidence: 81%

Randomized CRISPR-Cas Transcriptional Perturbation Screening Reveals Protective Genes against Alpha-Synuclein Toxicity

et al. 2017

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“…), and HSP31 (Tsai et al . ) reduced the aggregate formation and alleviated toxicity within α‐Syn over‐expressing cells. Furthermore, the co‐overexpression of HSP70 may provide additional benefits by reducing the secretion of toxic oligomers from axon terminals and thus suppressing extracellular mediated cell‐to‐cell transfer (Danzer et al .…”

Section: Cellular Models Of α‐Syn Pathologymentioning

confidence: 99%

“…Of these chaperones, the previously mentioned HSP family are perhaps the greatest studied and have been investigated in many neurodegenerative diseases (Paul and Mahanta 2014). Indeed the over-expression or induction of chaperones including HSP70 (Danzer et al 2011;Kilpatrick et al 2013), HSP27 (Outeiro et al 2006), and HSP31 (Tsai et al 2015) reduced the aggregate formation and alleviated toxicity within a-Syn over-expressing cells. Furthermore, the co-overexpression of HSP70 may provide additional benefits by reducing the secretion of toxic oligomers from axon terminals and thus suppressing extracellular mediated cell-to-cell transfer (Danzer et al 2011).…”

Section: Protein Aggregationmentioning

confidence: 99%

In vitro models of synucleinopathies: informing on molecular mechanisms and protective strategies

Marvian

Koss

Aliakbari

et al. 2019

Journal of Neurochemistry

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Alpha‐synuclein (α‐Syn) is a central player in Parkinson's disease (PD) and in a spectrum of neurodegenerative diseases collectively known as synucleinopathies. The protein was first associated with PD just over 20 years ago, when it was found to (i) be a major component of Lewy bodies and (ii) to be also associated with familial forms of PD. The characterization of α‐Syn pathology has been achieved through postmortem studies of human brains. However, the identification of toxic mechanisms associated with α‐Syn was only achieved through the use of experimental models. In vitro models are highly accessible, enable relatively rapid studies, and have been extensively employed to address α‐Syn‐associated neurodegeneration. Given the diversity of models used and the outcomes of the studies, a cumulative and comprehensive perspective emerges as indispensable to pave the way for further investigations. Here, we subdivided in vitro models of α‐Syn pathology into three major types: (i) models simulating α‐Syn fibrillization and the formation of different aggregated structures in vitro, (ii) models based on the intracellular expression of α‐Syn, reporting on pathogenic conditions and cellular dysfunctions induced, and (iii) models using extracellular treatment with α‐Syn aggregated species, reporting on sites of interaction and their downstream consequences. In summary, we review the underlying molecular mechanisms discovered and categorize protective strategies, in order to pave the way for future studies and the identification of effective therapeutic strategies. This article is part of the Special Issue “Synuclein”.

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“…αSYN is the neuropathological protein that is related to and is likely to contribute to the development of PD. Accumulation of αSYN could be increased under oxidative stress [105], which can be produced by increased CYP2E1 following exposure to alcohol [106] or MPTP [107], which is frequently used to develop animal models of PD [108]. Moreover, the gene encoding αSYN (SNCA) is identified as one of the most important genetic contributors to both familial and sporadic PD.…”

Section: Studies With Animal and Cell Culture Modelsmentioning

confidence: 99%

Role of Alcohol Drinking in Alzheimer’s Disease, Parkinson’s Disease, and Amyotrophic Lateral Sclerosis

Peng

Yang²,

Joshi

et al. 2020

IJMS

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Neurodegenerative diseases, including Alzheimer’s disease (AD), Parkinson’s disease (PD) and amyotrophic lateral sclerosis (ALS), increase as the population ages around the world. Environmental factors also play an important role in most cases. Alcohol consumption exists extensively and it acts as one of the environmental factors that promotes these neurodegenerative diseases. The brain is a major target for the actions of alcohol, and heavy alcohol consumption has long been associated with brain damage. Chronic alcohol intake leads to elevated glutamate-induced excitotoxicity, oxidative stress and permanent neuronal damage associated with malnutrition. The relationship and contributing mechanisms of alcohol with these three diseases are different. Epidemiological studies have reported a reduction in the prevalence of Alzheimer’s disease in individuals who drink low amounts of alcohol; low or moderate concentrations of ethanol protect against β-amyloid (Aβ) toxicity in hippocampal neurons; and excessive amounts of ethanol increase accumulation of Aβ and Tau phosphorylation. Alcohol has been suggested to be either protective of, or not associated with, PD. However, experimental animal studies indicate that chronic heavy alcohol consumption may have dopamine neurotoxic effects through the induction of Cytochrome P450 2E1 (CYP2E1) and an increase in the amount of α-Synuclein (αSYN) relevant to PD. The findings on the association between alcohol consumption and ALS are inconsistent; a recent population-based study suggests that alcohol drinking seems to not influence the risk of developing ALS. Additional research is needed to clarify the potential etiological involvement of alcohol intake in causing or resulting in major neurodegenerative diseases, which will eventually lead to potential therapeutics against these alcoholic neurodegenerative diseases.

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Hsp31 Is a Stress Response Chaperone That Intervenes in the Protein Misfolding Process

Cited by 38 publications

References 76 publications

Randomized CRISPR-Cas Transcriptional Perturbation Screening Reveals Protective Genes against Alpha-Synuclein Toxicity

Randomized CRISPR-Cas Transcriptional Perturbation Screening Reveals Protective Genes against Alpha-Synuclein Toxicity

In vitro models of synucleinopathies: informing on molecular mechanisms and protective strategies

Role of Alcohol Drinking in Alzheimer’s Disease, Parkinson’s Disease, and Amyotrophic Lateral Sclerosis

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