Sharma Laboratory

Sharma Laboratory researchers investigate the pathogenesis of age-dependent neurodegenerative diseases, including Alzheimer's and Parkinson's, at the cellular-molecular level, utilizing a combination of biochemistry, cellular biology, genetic mouse models, animal behavior and histochemistry. Neurodegenerative diseases are associated with age-dependent failure of protein homeostasis, or “proteostasis”, specifically within aggregation-prone proteins such as tau and alpha-synuclein. Sharma Lab investigators study the mechanisms that mediate proteostasis in neurons and how their failure over time leads to neurodegeneration.

Lab Projects

Tau Proteostasis by Hsc70 Co-Chaperones

Principal Investigator:

American Federation for Aging Research (AFAR) New Investigator Award in Alzheimer's Disease

Microtubules are tiny tubular structures in cells that act like conveyor belts, moving vesicles, granules, chromosomes, and organelles such as mitochondria via special attachment proteins. Tau protein molecules stabilize these microtubules. But when tau proteins become defective, pathologies of the nervous system (such as Alzheimer’s disease) can develop. Defective tau proteins accumulate in the form of aggregates in the neurons of Alzheimer’s disease patients and consequently lead to neuron loss and cognitive decline. The objective of Dr. Sharma’s research is to achieve a better understanding of the molecular machinery that suppresses tau aggregation in neurons. Dr. Sharma and his group will use biochemical, cell biological, and whole-animal approaches to investigate how Hsj1 (a co-chaperone protein) causes tau degradation, thus possibly reducing tau aggregation and pathology. They expect their research to give them a clear understanding, in molecular detail, of how Hsj1 acts to reduce tau in neurons. They also expect to clarify whether this action of Hsj1 protects against neurodegeneration driven by tau aggregation. Dr. Sharma’s research, if successful, could make a huge impact on the treatment of Alzheimer’s disease by informing therapeutic strategies that mimic or boost the activity of cellular tau-degrading mechanisms.

Tau Proteostasis by Cysteine String Protein-alpha (CSP-alpha)

Principal Investigator:

Alzheimer’s Association New Investigator Research Grant (NIRG)

Aggregation of microtubule-associated protein tau is a hallmark of age-dependent neurodegeneration in Alzheimer’s disease and other tauopathies. While tau mutations are strongly associated with some tauopathies (e.g. frontotemporal dementia), the vast majority of cases with tauopathic neurodegeneration do not result from tau mutations: for example, no tau mutation is known to cause Alzheimer’s disease. Thus, there is a critical need to understand why wild type tau fails to retain its native conformation, and forms pathogenic oligomers and aggregates. Our objective here is to delineate the molecular mechanism of tau proteostasis, and how this mechanism modifies tau aggregation and neurodegeneration. Based upon our preliminary data in combination with published studies, our central hypothesis is that tau aggregation and neurodegeneration are reduced by three proteostatic mechanisms: via structural stabilization by the CSPα/Hsc70 “foladase” complex, via turnover by the CHIP/Hsc70 “degradase” complex, and/or via disaggregation by the Hsp110/Hsc70 complex. At the completion of our studies, we expect to have (i) determined in molecular detail, how CSPα stabilizes tau and affects tau aggregation, (ii) included this novel activity in the overall context of tau proteostasis: which of CSPα, CHIP and/or Hsp110 is most effective at reducing tau aggregates while maintaining native tau, and (iii) determined in vivo how these proteostatic mechanisms protect against tau-driven neurodegeneration.

DnaJ co-chaperones which modify tau aggregation and neurodegeneration in Alzheimer's disease

Principal Investigator:

NIH/NIA (8/1/2016-5/31/2021)

The central goal of this project is to understand whether and how tau aggregation and neurodegeneration are affected by the activities of two neuronal chaperone machines: CSPα/Hsc70/SGT-foldase, which stabilizes tau and the Hsj1/Hsc70/CHIP-degradase which turns over tau.

Cellular mechanism of Adult Onset Neuronal Ceroid Lipofuscinosis (ANCL) caused by mutations in cysteine string protein-alpha (CSPalpha)

Principal Investigator:

NIH/NINDS (4/1/2017-3/31/2022)

The central goal of this project is to understand how mutations in synaptic chaperone CSPα, which cause Adult onset neuronal ceroid lipofuscinosis (ANCL), disrupt the function of CSPα in stabilizing the SNARE-protein SNAP-23; and how destabilization of SNAP-23 disrupts lysosomal pathology of ANCL. We also propose to rescue these defects using specific chemical chaperones.

Tau Proteostasis by Tau Proteostasis by Cysteine String Protein-alpha (CSPα)

Principal Investigator:

Alzheimer's Association New Investigator Research Grant

The central goal of this project is to understand how the synaptic co-chaperone protein CSPα affects the stability and aggregation of tau in neurons. An additional goal of this New Investigator Award is to encourage new PIs to generate data toward getting longer term funding.

Weill Cornell Medicine Helen & Robert Appel Alzheimer’s Disease Research Institute 413 E. 69th St. New York, NY 10021