ACTIVITY-INDUCED INHIBITOR OF DEATH GENES AS MOLECULAR TARGETS FOR SPINOCEREBELLAR ATAXIA TYPE 2 AND 3

Spinocerebellar ataxia types 2 and 3 (SCA2/3) are rare autosomal-dominant neurodegenerative disorders caused by pathogenic CAG repeat expansions and currently lack disease-modifying therapies. A major barrier to therapeutic innovation is the limited understanding of cerebellar molecular programs that normally promote neuronal resilience and how these programs fail in disease. Activity-regulated Inhibitors of Death (AID) genes encode transcription factors with neuroprotective effects in other neurological disorders, but their role in cerebellar physiology and SCA pathogenesis remains unclear.
Here, we investigate two activity-regulated transcription factors, as intrinsic neuroprotective regulators in the cerebellum. We show that both genes are induced by motor activity in the cerebellum, yet are downregulated in two SCA mouse models, suggesting a disrupted resilience program. Functionally, silencing these genes in wild-type mice causes severe motor impairments and increased mortality, demonstrating that these factors are essential for cerebellar integrity and survival. Conversely, gene augmentation strategies mitigated motor deficits in the SCA mouse models, indicating preclinical potential.
We are dissecting disease-relevant circuit dysfunction by probing granule neuron-to-cell Purkinje communication, two neuronal populations that degenerate in SCAs and how gene augmentation strategies can mitigate these deficits. Overall, our findings support a model in which SCA2/3 involves failure of an activity-driven neuroprotective transcriptional program. Restoring this endogenous resilience pathway via gene therapy represents a strategy with potential relevance for the group of polyglutamine ataxias.