Investigating Lysosomal Dysfunction in Ageing and Neurodegeneration

Lysosomes are key cellular organelles that degrade and recycle macromolecules, act as signalling hubs and are implicated in many diseases including Parkinson’s disease (PD) and Alzheimer’s dementia (AD) where old age is a major risk factor. Studying lysosomal biology and dysfunction in human diseases has been challenging because lysosomes represent less than 3% of the total cell volume, such that changes in lysosomal content are hardly detected using traditional whole tissue/cell measurements. To overcome this, we have refined a recently developed approach for the rapid immunoaffinity purification (IP) of intact lysosomes using a recombinant tag on the external lysosomal transmembrane protein for use in the endogenous system and use in human peripheral blood mononuclear cells. In this project, the plan is to characterise the lysosomal content in terms of proteins, lipids and metabolites in cells derived from peripheral blood from people with PD /AD and healthy controls. This expected outcome is to delineate disease specific signatures that can be exploited for biomarker development and novel treatment strategies.

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