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Protein quality control and neurodegenerative disease - to test the hypothesis that BAG6 contributes to the quality control of a range of disease-linked proteins in the cytosol


Project Description

Misfolded proteins represent a continuous threat to cell viability, which if allowed to accumulate can disrupt cellular function and induce cell death [1]. Therefore, cells possess quality control systems in multiple subcellular compartments in order to identify and eliminate such aberrant polypeptides. A range of factors including genetic mutation, environmental conditions and ageing can increase the rate of protein misfolding, thereby overwhelming quality control systems and triggering accumulation of abnormal proteins. Indeed, many neurodegenerative diseases, such as frontotemporal lobar degeneration (FTLD), Amyotrophic Lateral Sclerosis (ALS), Parkinson’s disease and Alzheimer’s disease, are characterised by the accumulation of cytoplasmic aggregates composed of structurally abnormal proteins [2]. Thus, understanding the molecular mechanisms that mediate quality control and degradation of abnormal proteins in the cytoplasm are directly relevant to human diseases caused by protein misfolding and aggregation. Recent work from our lab and others has identified BAG6 as a key component of the cytoplasmic quality control machinery [3]. BAG6 is a multifunctional protein, which recognises proteins possessing exposed regions of hydrophobicity and facilitates their degradation. Within the cytosol, such proteins have an increased risk of aggregation and/or inappropriate interactions, and many misfolded proteins implicated in human disease contain highly hydrophobic region(s). The aim of this project is to test the hypothesis that BAG6 contributes to the quality control of a range of disease-linked proteins in the cytosol. The project brings together expertise in biochemistry and cell biology, computational biology and the molecular genetics of neurodegenerative disease. Training in these areas will be provided by the relevant supervisors, and as such the student will benefit from working in a highly interdisciplinary environment provided within these laboratories.

Funding Notes

This project has a Band 2 fee. Details of our different fee bands can be found on our website (View Website). For information on how to apply for this project, please visit the Faculty of Biology, Medicine and Health Doctoral Academy website (View Website).

Informal enquiries may be made directly to the primary supervisor.

References

Hartl et al (2011). Molecular chaperones in protein folding and proteostasis. Nature. 475: 324-32.

Soto (2003). Unfolding the role of protein misfolding in neurodegenerative diseases. Nat Rev Neurosci. 4: 49-60.

Ast & Schuldiner (2011). Protein degradation: BAGging up the trash. Curr Biol. 21: R692-5.

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