Therapeutic modulation of autophagy–NAD axis in iPSC-derived neuronal models of rare neurodegenerative diseases


   Institute of Cancer and Genomic Sciences

This project is no longer listed on FindAPhD.com and may not be available.

Click here to search FindAPhD.com for PhD studentship opportunities
  Dr S Sarkar, Dr T G Barrett, Dr D Tennant  No more applications being accepted  Competition Funded PhD Project (Students Worldwide)

About the Project

Informal enquiries should be directed to the project supervisor Dr Sovan Sarkar ([Email Address Removed]); see the lab website for further details on research: https://www.sovansarkarlab.com/   

Person Specification

Applicants should have a strong background in cell culture and cell biology, and ideally a background in human pluripotent stem cell culture and neuronal differentiation. They should have a commitment to research in biology and hold or realistically expect to obtain at least an Upper Second Class Honours Degree in Biological or Biomedical Science related courses. 

Project Details:

Nervous system disorders include common diseases like dementia, and rare genetic disorders that are often childhood-onset neurodegeneration. However, finding cure for rare diseases is challenging because of their rarity and limited knowledge of the disease process. We aim to establish shared disease mechanism for developing a common therapy to improve the health of children with rare, early-onset forms of neurodegeneration. Autophagy, a cellular homeostatic process essential for cell survival and human health, is commonly deregulated in several neurodegenerative diseases. We recently showed that loss of autophagy reduces neuronal cell survival via depletion of a metabolite called nicotinamide adenine dinucleotide (NAD), which mediates mitochondrial depolarisation and cell death.

In this project, we will utilize disease-affected cortical neurons generated from patient-derived induced pluripotent stem cells (iPSCs) to study cellular and metabolic perturbations underlying autophagy dysfunction for establishing defective autophagy-NAD axis as a shared patho-mechanism in two rare diseases. We will then test a panel of compounds, such as autophagy and NAD enhancers that are FDA-approved drugs or used as nutritional supplements, to rescue disease-relevant phenotypes and improve the survival of patient iPSC-derived neurons. Since autophagy and NAD deficits are found in a range of neurodegenerative disease, our therapeutic approach has the potential for generalisability to other rare or common neurodegenerative conditions.

The project will involve iPSC culture and neuronal differentiation; metabolomics; high-content imaging and confocal microscopy; drug testing; cell biology and biochemical studies for autophagy, NAD, mitochondrial function, proteostasis, and cell death; data analysis and statistical methods.

To apply:

Please click on the institution website which will take you to the MRC AIM website which contains full information and the application forms.

Please ensure your application is submitted by the deadline of midday (GM) Friday 12 January 2024 as late applications will not be considered.

Biological Sciences (4) Medicine (26)

Funding Notes

This is a fully funded studentship provided by the Medical Research Council.
If you are successful, you will receive a stipend (currently £18,622 per year for 2023/24) and a tuition fee waiver for 4 years.
Successful candidates will also receive an allowance for a laptop, a travel and conference allowance and an allowance for laboratory/PhD running costs.

References

For full list of publications of the supervisor, see: https://www.sovansarkarlab.com/publications.html
[1] NAD depletion mediates cytotoxicity in human neurons with autophagy deficiency. Sun C.*, Seranova E.*, Cohen M.A.*, Chipara M., Roberts J., Astuti D., Palhegyi A.M., Acharjee A., Sedlackova L., Kataura T., Otten E.G., Panda P.K., Reyna S.L., Korsgen M.E., Kauffman K.J., Huerta-Uribe A., Zatyka M., Silva L.F.S.E., Torresi J., Zhang S., Hughes G.W., Ward C., Kuechler E.R., Cartwright D., Trushin S., Trushina E., Sahay G., Buganim Y., Lavery G.G., Gsponer J., Anderson D.G., Frickel E.M., Rosenstock T.R., Barrett T., Maddocks O.D.K., Tennant D.A., Wang H., Jaenisch R., Korolchuk V.I.†, Sarkar S.† Cell Reports 42(5): 112372 (2023) [PMID: 37086404].
[2] Depletion of WFS1 compromises mitochondrial function in hiPSC-derived neuronal models of Wolfram syndrome. Zatyka M.*, Rosenstock T.R.*, Sun C., Palhegyi A.M., Hughes G.W., Reyna S.L., Astuti D., Maio A.D., Sciauvaud A., Korsgen M.E., Stanulovic V., Kocak G., Rak M., Pourtoy-Brasselet S., Winter K., Varga T., Jarrige M., Polveche H., Correia J., Frickel E.M., Hoogenkamp M., Ward D.G., Aubry L., Barrett T., Sarkar S.† Stem Cell Reports 18(5): 1090-1106 (2023) [PMID: 37163979].
[3] The autophagy-NAD axis in longevity and disease. Wilson N.*, Kataura T.*, Korsgen M.E., Sun C., Sarkar S.†, Korolchuk V.I.† Trends in Cell Biology 33(9): 788-802 (2023) [PMID: 36878731].
[4] Autophagy promotes cell survival by maintaining NAD levels. Kataura T.*, Sedlackova L.*, Otten E.G., Kumari R., Shapira D., Scialo F., Stefanatos R., Ishikawa K., Kelly G., Seranova E., Sun C., Maetzel D., Kenneth N., Trushin S., Zhang T., Trushina E., Bascom C.C., Tasseff R., Isfort R.J., Oblong J.E., Miwa S., Lazarou M., Jaenisch R., Imoto M., Saiki S., Papamichos-Chronakis M., Manjithaya R., Maddocks O.D.K., Sanz A., Sarkar S.†, Korolchuk V.I.† Developmental Cell 57(22): 2584-2598 (2022) [PMID: 36413951].
[5] Human induced pluripotent stem cell models of neurodegenerative disorders for studying the biomedical implications of autophagy. Seranova E.*, Palhegyi A.M.*, Verma S., Dimova S., Lasry R., Naama M., Sun C., Barrett T., Rosenstock T.R., Kumar D., Cohen M.A., Buganim Y., Sarkar S.†
Journal of Molecular Biology 432(8): 2754-2798 (2020) [PMID: 32044344].
[6] Genetic and chemical correction of cholesterol accumulation and impaired autophagy in hepatic and neural cells derived from Niemann-Pick iPS cells. Maetzel D.*, Sarkar S.*, Wang H.*, Abi-Mosleh L., Xu P., Cheng A.W., Gao Q., Mitalipova M., Jaenisch R. Stem Cell Reports 2(6): 866-880 (2014) [PMID: 24936472].
[7] Impaired autophagy in the lipid storage disorder Niemann-Pick type C1 disease. Sarkar S., Carroll B., Buganim Y., Maetzel D., Ng A.H.M., Cassady J.P., Cohen M.A., Chakraborty S., Wang H., Spooner E., Ploegh H., Gsponer J., Korolchuk V.I., Jaenisch R. Cell Reports 5(5): 1302-1315 (2013) [PMID: 24290752].
[8] Small molecules enhance autophagy and reduce toxicity in Huntington’s disease models.
Sarkar S.*, Perlstein E.O.*, Imarisio S., Pineau S., Cordenier A., Maglathlin R.L., Webster J.A., Lewis T.A., O’Kane C.J., Schreiber S.L., Rubinsztein D.C. Nature Chemical Biology 3(6): 331-338 (2007) [PMID: 17486044].
*Equal contribution; †Corresponding author

Where will I study?