Regulatory chaperone complexes in neurodegenerative diseases: a perspective on therapeutic intervention
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Published on: June 7, 2020
Aaron Carman, Sarah Kishinevsky, John Koren
1Molecular Pharmacology & Chemistry, Sloan-Kettering Institute, Associate Attending, Breast Cancer Service, Department of Medicine, Memorial Hospital, Memorial Sloan- Kettering Cancer Center, ZRB2103, Associate Professor, Weill Graduate School of Medical Sciences, New York, USA. chiosisg@MSKCC.ORG.
Abstract:
Protein folding, protein degradation, and protein stability are regulated by the molecular chaperones. Under pathogenic conditions, aberrant proteins can be dysfunctional, unregulated, or pathogenically mutated. These aberrant proteins are triaged by the chaperone network for the maintenance of cellular homeostasis. These species, called chaperone client proteins, include the pathogenic factors of numerous neurodegenerative disorders, including tau in Alzheimer's disease, α-synuclein and LRRK2 in Parkinson's disease, SOD-1, TDP-43 and FUS in amyotrophic lateral sclerosis, and polyQ-expanded proteins such as huntingtin in Huntington's disease. In depth study of two molecular chaperones, Hsp90 and Hsc70, has led to a greater understanding of aberrant client fate and how retarding the chaperone system can promote clearance of these pathogenic clients. Here we discuss how chaperone interactions and small molecule inhibitors can regulate the burden of aberrant client signaling in these neurological disorders.
Insights
Molecular chaperones regulate protein homeostasis. Targeting chaperone systems, like Hsp90 and Hsc70, can help clear aberrant proteins linked to neurodegenerative diseases such as Alzheimer
Area of Science:
- Molecular biology
- Neuroscience
- Biochemistry
Background:
- Molecular chaperones are crucial for protein folding, degradation, and stability, maintaining cellular homeostasis.
- Aberrant proteins, including those in neurodegenerative diseases, are managed by the chaperone network.
- Chaperone client proteins are implicated in Alzheimer's, Parkinson's, ALS, and Huntington's disease.
Purpose of the Study:
- To explore the role of molecular chaperones in managing aberrant proteins in neurodegenerative disorders.
- To investigate how Hsp90 and Hsc70 influence the fate of pathogenic client proteins.
- To discuss the potential of targeting chaperone systems for therapeutic intervention.
Main Methods:
- Review and synthesis of existing research on molecular chaperones and neurodegenerative diseases.
- Focus on the mechanisms of Hsp90 and Hsc70 in relation to client protein triage.
- Analysis of small molecule inhibitors that modulate chaperone activity.
Main Results:
- Aberrant proteins in neurodegenerative diseases are recognized and processed by the chaperone network.
- Understanding chaperone interactions provides insights into pathogenic client protein fate.
- Retarding chaperone system activity can promote the clearance of disease-associated proteins.
Conclusions:
- Molecular chaperones play a critical role in cellular homeostasis by managing aberrant proteins.
- Targeting chaperone interactions and activity with small molecules offers a potential therapeutic strategy for neurodegenerative disorders.
- Further research into chaperone regulation could lead to novel treatments for diseases like Alzheimer's and Parkinson's.
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