Spinocerebellar Ataxias (SCAs) are inherited neurodegenerative disorders causing progressive decline in balance, speech, and gait, often resulting in premature death due to brainstem dysfunction. The majority of SCAs are trinucleotide repeat expansion diseases resulting in polyglutamine aggregation. While genetic therapies are being investigated for some SCAs, these modalities may not address already present symptoms and are restricted by design to a single gene and therefore disease. Despite genetically unique origins, the clinical features of many SCAs are similar, suggesting shared key downstream pathogenic events. One such hallmark of many SCAs is abnormal spiking activity in cerebellar Purkinje cells (PCs), which correlates with motor decline and precedes cellular degeneration. Aberrant PC spiking derives mainly from decreased activity in potassium channels, augmentation of which improves motor function and delays cellular atrophy. In this talk, I will discuss my efforts in establishing a drug-discovery pipeline against dysfunctional circuitry in the SCAs, from high-throughput screening (HTS), validation in mouse models, and early pharmacological characterization. Such an approach may be complementary to genetic strategies against the root cause and greatly advance our care of SCA patients.
“Targeting Impaired Circuitry for Therapeutic Rescue in Spinocerebellar Ataxia”
