Manu Sharma

Our Mission

My lab investigates pathogenesis of age-dependent neurodegenerative diseases, like Alzheimer's disease and Parkinson's disease, at the cellular-molecular level. To study these diseases, we combine biochemistry, cell biology, mouse genetic models and mouse behavior.

Short-term Goals

Neurodegenerative diseases are associated with varied genetic and environmental factors, yet age remains a universal risk factor. Age-associated failure of protein homeostasis, or “proteostasis”, causes disease-linked proteins to misfold into non-physiological oligomers and aggregates, producing a myriad of cellular dysfunctions. Long lifetime of a neuron enhances the need for proteostatic mechanisms, such as molecular chaperones that stabilize native protein folds and degradation pathways that eliminate misfolded proteins. My lab is interested in the mechanisms that mediate proteostasis in neurons and how their failure over time leads to neurodegeneration.

We are investigating this topic by:
a) Studying how proteostasis of Tau protein is regulated by two co-chaperones of Hsc70: CHIP (C-terminus of Hsc/Hsp70 interacting protein) and CSP-α (cysteine string protein-α).
b) Investigating how neurodegeneration is caused by recently found human mutations in CSP-α which cause neuronal ceroid lipofuscinosis, an adult-onset neurodegenerative disorder.
c) Comparing lysosomes from brains of normal mice and from neurodegenerative mouse models to identify changes that accompany the decline of neuronal proteostasis.

Long-term Goals

Our research will uncover proteostatic mechanisms in neurons which allow them to live and function for a lifetime, and how these mechanisms fail in aging neurons. Understanding neuronal proteostasis in health and disease may lead to treatment strategies for multiple neurodegenerative disorders, like Parkinson’s disease and Alzheimer’s disease, which share age-dependent proteostatic defects.

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Sharma Lab