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The role of protein aggregates in sarcopenia and muscle aging


   Biosciences Institute

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  Dr Michael John Keogh, Prof Volker Straub, Dr I Karakesisoglou, Dr Christopher Morris  No more applications being accepted  Competition Funded PhD Project (Students Worldwide)

About the Project

The process of aging is associated with a progressive decline in many physiological functions, impacting quality of life for elderly individuals. Within muscles, the loss of mass and function with age is termed sarcopenia, and represents a major public health problem with enormous clinical and societal consequences. The cellular mechanisms underlying sarcopenia and aging remain unclear, and this lack of understanding has impaired our ability to develop treatments.

Aggregated proteins have been almost universally observed in aging tissues in many species, though whether they are an epiphenomenon of aging or contribute directly to cellular and functional impairment is unknown. Insight from genetic diseases such as myofibrillar myopathies (MFM) in which an excess of muscle protein aggregates develop alongside progressive muscle wasting suggest that protein aggregates, at least in muscle, may directly contribute to aging and sarcopenia. If true, then reducing protein accumulation within muscles may represent a novel treatment paradigm for sarcopenia.

Secondly, work within the central nervous system has shown that such aggregated proteins do not always accumulate independently within cells. Some proteins spread from cell-to-cell in a prion-like or ‘metastatic’ fashion particularly in neurons, as observed in diseases such as Alzheimer’s disease and Parkinson’s disease. If this were also the case in aging muscle it would transform the way we understand the process of muscle aging and alter our approach to treatment.

In this project, you will have the opportunity to use cutting-edge techniques such as mass spectrometry, imaging mass cytometry and nuclear magnetic resonance fibrillisation assays to identify and quantify protein aggregates in post-mortem aged human muscle tissues and from individuals with protein aggregation disorders (MFM) to understand and quantify protein aggregate formation. Thereafter, you will study how aggregates affect cell stiffness and elucidate their impact on nuclear structure, composition, motility, and positioning which are fundamental for the fitness and mechano-responsiveness of muscle cells. Finally, you will build novel 3D cell culture models to determine whether and how human muscle can develop and transmit identified proteins between them. To achieve this you will work across three internationally recognised laboratories who study muscle diseases, aging and protein aggregation respectively. Harnessing the experience and resources of these successful groups will allow you to develop an extensive state-of-the-art skill-set supported by highly successful and encouraging laboratory groups to tackle a problem of major scientific importance that offers outstanding future career opportunities.

The studentship should be commenced before the end of 2022.

 HOW TO APPLY

Applications should be made by emailing [Email Address Removed] with:

·      a CV (including contact details of at least two academic (or other relevant) referees);

·       a covering letter – clearly stating your first choice project, and optionally 2nd ranked project, as well as including whatever additional information you feel is pertinent to your application; you may wish to indicate, for example, why you are particularly interested in the selected project(s) and at the selected University;

·      copies of your relevant undergraduate degree transcripts and certificates;

·      a copy of your passport (photo page).

A GUIDE TO THE FORMAT REQUIRED FOR THE APPLICATION DOCUMENTS IS AVAILABLE AT https://www.nld-dtp.org.uk/how-apply. Applications not meeting these criteria may be rejected.

In addition to the above items, please email a completed copy of the Additional Details Form (as a Word document) to [Email Address Removed]. A blank copy of this form can be found at: https://www.nld-dtp.org.uk/how-apply.

Informal enquiries may be made to [Email Address Removed]. The closing date for applications is Friday 8th July 2022 at 12noon (UK time).


Funding Notes

Studentships are funded by the Biotechnology and Biological Sciences Research Council (BBSRC) for 4 years. Funding will cover tuition fees at the UK rate only, a Research Training and Support Grant (RTSG) and stipend. We aim to support the most outstanding applicants from outside the UK and are able to offer a limited number of bursaries that will enable full studentships to be awarded to international applicants. These full studentships will only be awarded to exceptional quality candidates, due to the competitive nature of this scheme.

References

1) Neuropathological and biochemical investigation of Hereditary Ferritinopathy cases with ferritin light chain mutation: Prominent protein aggregation in the absence of major mitochondrial or oxidative stress. Neuropathol Appl Neurobiol. 2021 Feb;47(1):26-42
2) Assessment of disease progression in dysferlinopathy: A 1-year cohort study. Neurology. 2019 Jan 9.
3) Culturing Keratinocytes on Biomimetic Substrates Facilitates Improved Epidermal Assembly In Vitro. Cells, 2021, 10(5):1177. doi: 10.3390/cells10051177. PMID: 34066027; PMCID: PMC8151809.
4) Nesprin-2 giant safeguards nuclear envelope architecture in LMNA S143F progeria cells. Hum. Mol. Genet. 2007, 16, 2944-2959.
5) Altered ceramide metabolism is a feature in the extracellular vesicle-mediated spread of alpha-synuclein in Lewy body disorders. Acta Neuropathol. 2021 Sep 13. doi: 10.1007/s00401-021-02367-3.
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