Most neurodegenerative disorders are marked the accumulation of misfolded and aggregated proteins in the brain, particularly within neurons and with age. Our laboratory seeks to understand how the neuronal protein homeostasis (proteostasis) network defends against age-related neurodegenerative diseases. These diseases include repeat expansion diseases (Huntington's disease, spinocerebellar ataxia, neuronal intranuclear inclusion disease), amyotrophic lateral sclerosis, and frontotemporal lobar degeneration. Our work integrates high-throughput CRISPR-based functional genomics, transcriptomics, microscopy/imaging, proteomic, and biochemical techniques to study proteostasis pathways and disease mechanisms in cell models (including iPSC-derived neurons), mouse models, and human neuropathologic tissues.
Current projects
a. Mapping neuronal proteostasis pathways in the Huntington's disease, neuronal intranuclear inclusion disease, and frontotemporal dementia/amyotrophic lateral sclerosis.
b. Understanding the molecular and biochemical/biophysical basis of chaperone selectivity for different disease-associated proteins
c. Dissecting regional and cell-type specific vulnerability in diseases caused by chaperone mutations
d. Elucidating nuclear proteostasis pathways and mechanisms of nuclear proteotoxicity in repeat expansion diseases
e. Defining genetic modifiers and mechanisms of TDP-43-mediated toxicity in aging and neurodegeneration.