Sharma Laboratory

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.

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.

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.

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.

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.