Project ID NS-MH2024_36


Co Supervisor 1A Institute of Psychiatry, Psychology & Neuroscience, School of Neuroscience, Department of Basic & Clinical NeuroscienceWebsite

Co Supervisor 1B Institute of Psychiatry, Psychology & Neuroscience, School of Neuroscience, Department of Basic & Clinical NeuroscienceWebsite

Chaperones as mediators of astrocyte-neuron protection in Alzheimer’s disease

Neurodegenerative diseases are currently incurable diseases that result in progressive neuronal degeneration. With the increase in the ageing population, it is estimated that 1 in 3 people born today will develop dementia or related disorders. Protein aggregation is a common hallmark to any neurodegenerative disease as a consequence of a failure of proteostasis mechanisms. These mechanisms include a network of chaperones that prevent protein misfolding and research into these mechanisms is essential to understand the underlying factors in neurodegeneration and to work towards effective therapeutic strategies. While mostly studied in neuronal cells, our work aims to investigate these mechanisms in the function of glial cells in the brain and in glia-neuron communication in neurodegenerative diseases.

Alzheimer’s disease and other neurodegenerative diseases are characterized by high levels of chaperones of the family of small Heat Shock Proteins (sHSP), mostly attributed to their increased levels in glial cells. The chaperone function of sHSPs is modulated by posttranslational modifications including phosphorylation and oligomerization. However, the impact of these modifications on their function in astrocytes and in the astrocyte-neuron axis in Alzheimer’s disease remains to be elucidated. This project aims to shed light into the changes that characterize sHSPs in disease brain, and to further provide mechanistic insights into the contribution of reactive astrocytes to Alzheimer’s disease.

Year 1. Characterize chaperone posttranslational modifications in the brain of Alzheimer’s disease and other tauopathies
Year 2. Investigate chaperone posttranslational modifications in reactive astrocytes
Year 3. Study how chaperone modifications can modulate protein aggregation in neurons

To address this, the PhD student will use post-mortem human brain tissue from the London Neurodegenerative Diseases Brain Bank, which is coordinated by the co-supervisor Dr Claire Troakes, as well as primary mouse astrocyte cultures and organotypic brain slice cultures, used in Dr Maria Jimenez-Sanchez lab.

Representative Publications

Matafora V, Gorb A, Noble W, Bachi A, Perez-Nievas BG, Jimenez-Sanchez M. Proteomics of the astrocyte secretome reveals changes in response to soluble oligomeric Aß. J Neurochem. 2023. doi: 10.1101/2023.01.18.523916.

Jimenez-Sanchez M, Lam W, Hannus M, … and Rubinsztein DC. siRNA screen identifies QPCT as a druggable target for Huntington’s disease. Nat chem biol. 2015. doi: 10.1038/nchembio.1790

King A, Szekely B, Calapkulu E, Ali H, Rios F, Jones S, Troakes C The Increased Densities, But Different Distributions, of Both C3 and S100A10 Immunopositive Astrocyte-Like Cells in Alzheimer’s Disease Brains Suggest Possible Roles for Both A1 and A2 Astrocytes in the Disease Pathogenesis. Brain Sci. 2020 Jul 31;10(8):503. doi: 10.3390/brainsci10080503.

Troakes C, Smyth R, Noor F, Maekawa S, Killick R, King A, Al-Sarraj S Clusterin expression is upregulated following acute head injury and localizes to astrocytes in old head injury. Neuropathology. 2017 Feb;37(1):12-24. doi: 10.1111/neup.12320.