Neurodegenerative disorders, such as Alzheimer’s disease (AD), Huntington’s disease (HD) and Parkinson’s disease (PD), affect millions of people worldwide. Regardless of numerous attempts to find a treatment approach, therapeutics for these devastating diseases is yet to be discovered. One of the common pathological hallmarks of most age-related neurodegenerative disorders is the accumulation of mutant disease proteins as inclusion bodies. Appearance of aggregates of the misfolded mutant disease proteins suggest that cells are unable to efficiently degrade them, and failure of clearance leads to the severe disturbances of the cellular protein quality control system. Furthermore, the cellular ability to maintain protein homeostasis declines with age. Therefore the mechanism that restores protein homeostasis either by up-regulating the function of chaperones or enhancing the clearance of mutant disease proteins could be promising therapeutic approach.
In my laboratory, we are using HD and AD as a model system to understand the mechanistic basis of impaired protein homeostasis and how that can be restored. We have reported that Ube3a function as a cellular protein quality control ubiquitin ligase and involved in the clearance of misfolded disease proteins (J. Biol. Chem., 2008, 2009 and Neurobiol. Aging,2013). Deficiency of Ube3a in HD mice brain also increased global aggregate load and aggravated HD pathogenesis (Hum. Mol. Genet., 2014). In collaboration with Scientist at IACS, Kolkata, we are also using nanoparticle-based strategy to prevent fibrillation and aggregation of amyloid proteins (ACS Appl. Mat. Inter, 2016, 2017).
My laboratory also uses biochemical, cell biological and genetic approaches to understand the physiological function of Ube3a and how its gain as well as loss of function is linked with autism and autism spectrum disorders. We are also screening pharmacological inducers of Ube3a, which might be useful in the therapy of learning and memory disorders.
Restoration of Protein Quality Control as a Therapeutic Strategy to Combat Age-associated Neurodegenerative Disorders ISIRD, SRIC
Ube3a as a Therapeutic of Huntingtons Disease DBT, NEW DELHI
Area of Research: Auditory Neurophysiology
Akriti Baby Kanth
Area of Research: Neurodegenerative disease