Science

Despite our improved ability to recognize and diagnose neurodegenerative diseases, there is a disproportionate lack of effective treatments, highlighting the need to reconsider traditional strategies. While convention has rightfully emphasized these diseases as proteinopathies, often from a single genetic mutation, that approach has not led to many patient interventions. With a focus on cerebellar ataxia as a prototype, we propose reframing neurodegeneration as a circuit-based disorder.

Our group uses a broad array of techniques: from mammalian tissue culture and high throughput screening, to electrophysiology from slice recording, to behavioral analysis of transgenic mouse models of ataxia. 

Advancing BK Channel Activators for Therapeutic Rescue in SCAs 1 and 2

Abnormal Purkinje cell (PC) firing is a hallmark of many SCAs. It also correlates very tightly with onset of motor dysfunction in mouse models and precedes cellular degeneration, confirming the theory that "cells get sick and malfunction before they die". Through transcriptomics and electrophysiological studies, it is clear that  slow and irregular PC firing derives from diminished expression and function of large conductance (BK) potassium channels. 

We have identified lead molecules that activate BK channels under ataxia-like cellular conditions and are working with Medicinal Chemistry to generate novel and proprietary analogs for improved potency and pharmacokinetic parameters. Current work involves screening, validating, and characterizing these novel compounds, and preparing for in vivo analysis.

Defining Mechanisms of Exercise-Induced Benefits in Cerebellar Ataxias

The single proven clinical intervention in human SCA patients is robust cardiovascular exercise. While the benefits are clear, the mechanisms are not. Defining these pathways more explicitly may help us design pharmacomimetics of exercise for a patient population disabled from disease. 

We have identified that unlimited cardiovascular exercise, using in-cage running wheels, rescues motor ataxia in SCA1 mice and improves some of the electrophysiological properties of PCs. Further, exercise appears to generate transcriptional changes within the cerebellum. Further analysis of these changes using a variety of approaches is being explored to define the molecular mechanisms at work.