The focus of my research laboratory is to explore the pathogenic processes and identify potential therapeutic strategies for neurodegenerative diseases, with a special emphasis on diseases resulting in ataxia. We leverage both cell culture and transgenic mouse models, complemented by human tissue and biofluid samples, to deepen our understanding of these neurodegenerative disorders. Our methodologies include surgical procedures, genetic analysis, imaging techniques, along with molecular and cellular biology techniques.

MECHANISTIC INSIGHT INTO SCA3 DISEASE PATHOGENESIS:
Due to the selective degeneration of neuronal populations, early research in polyQ disorders has taken a neuron-centric point of view. It is important to note, however, that glial cells, once only considered secondary supporting cells, are now recognized as vital components of the CNS that contribute greatly to neuronal health and contributors to neurodegenerative disease. From our longitudinal RNAseq SCA3 mouse studies, we identified oligodendrocyte myelination and sterol biosynthesis to be major pathways or cellular processes dysregulated at early brainstem stages in our SCA3 mouse model that are rescued by ASO therapy. In the past few years (funded by an R01 NS122751; 2021-2026), my lab has defined how widespread oligodendrocyte dysfunction is in SCA3 using a variety of cell, mouse models, and human tissue samples using biochemical and histological analyses. Two current research directions under this focus are 1) the development of novel SCA3 conditional mouse models to determine the extent that mutant ATXN3 expression elicits oligodendrocyte dysfunction and contributions to disease phenotypes and 2) investigations into the molecular mechanisms underlying oligodendrocyte dysfunction in SCA3 using aforementioned models and techniques. By defining oligodendrocytes’ role in SCA3 disease, my lab will answer whether this vulnerable cell type needs to be a target of emerging SCA3 therapies.

BIOMARKER DEVELOPMENT FOR SCA3:
Several treatment strategies for ataxias inspired by basic science laboratories, including my own, are ripe for testing in the clinic. Unfortunately, we do not have sensitive or specific biomarkers for i) predicting disease course in SCAs, ii) monitoring disease severity/outcome, iii) tracking response in clinical trials, or iv) improving the timing of therapeutic interventions. We previously collaborated with Dr. Gülin Öz through a funded NIH R21 (NS111154; 2019-2022) to develop MRS biomarkers that are correlated with SCA3 disease progression and with ASO-mediated reversal of pathology and behavior in mice. My lab conducted multiplexed protein studies with banked SCA3 plasma samples and found numerous novel proteins that can differentiate between symptomatic SCA3 patients and healthy individuals. In our data, we confirmed changes in neurofilament light (NfL), which currently serves as the benchmark plasma biomarker for predicting the onset and progression of SCA3 disease. Additionally, we’ve begun validating these biomarkers in our SCA3 mouse models for preclinical development. We are currently assessing/modeling plasma biomarkers for tracking disease progression and treatment response. We believe this work can help identify biomarkers that can enable trials to be powered with smaller sample sizes and provide objective measures for determining disease onset, progression, and therapeutic response more precisely.

THERAPEUTIC DEVELOPMENT FOR SCA3:
Since expression of the mutant ATXN3 protein is an early and necessary step in SCA3 disease pathogenesis, strategies to reduce expression of the disease gene or enhance clearance itself are high on the list of potential therapies. The lab is pursuing preclinical research programs targeting ATXN3 using antisense oligonucleotide and viral-mediate RNAi approaches. Additionally, we have therapeutic studies arising from our mechanistic programs in the lab.