Neurodegenerative diseases (NDs) are debilitating conditions that stem from the selective dysfunction and loss of neurons. In NDs such as Parkinson’s disease (PD), Alzheimer’s disease (AD), Amyotrophic lateral sclerosis (ALS) and Spinocerebellar ataxia type 1 (SCA1), vulnerable neuronal populations are lost in specific regions of the CNS. A commonality among NDs is that symptoms typically manifest in the fifth or sixth decade of life. There is presently no cure or therapeutic intervention that can reverse or halt the progression of NDs. In select cases of NDs, such as ALS, current therapy acts to prolong life for a brief period (<6 months). A major hindrance to the development of therapies for NDs is that the pathomechanisms underlying these diseases are not well understood. A common finding in NDs, is that neuronal dysfunction and pathology often significantly precedes overt clinical symptoms.
Research efforts in our lab are primarily focused on understanding pathomechanisms that drive neurodegeneration from circuits to molecular and cellular pathology. In particular, we are interested in examining how changes in cerebellar circuitry modulate or initiate degeneration in SCA1, a fatal cerebellar ND that results in progressive ataxia, dysarthria and the degeneration of cerebellar neurons. Employing conditional mouse models, proteomics, transcriptomics, pharmacogenetics, connectomics, in vivo calcium imaging, and behavioral readouts, we are deciphering how early alteration in the cerebellar circuitry governs disease onset and progression. Another major area of research is in generating human iPSC-derived in vitro models of ALS, a fatal motor neuron disease that results in paralysis and death typically within 4-5 years of disease onset. Finding efficacious therapy for ALS, most cases of which are sporadic and genetically heterogeneous, has been hampered by the lack of relevant pre-clinical models. Our aim is to derive human motor neurons from skin fibroblasts of both familial and sporadic ALS as well as control patients using cellular reprogramming. This undertaking will provide us with a relevant ALS platform to screen small molecule compound libraries and identify molecules that are able to reduce cellular and axonal-stress and protect motor neurons from degeneration.