Ataxia: Circuit deficits in the cerebellum trigger cell death

In their new study, Sabine Liebscher, Smita Saxena and their teams identify deficits in circuits of the cerebellum as important trigger of Spinocerebellar Ataxia Type 1.

Spinocerebellar Ataxia Type 1 (SCA1) is a rare neurodegenerative disorder that typically occurs in adulthood. Main symptoms are gait disturbances, difficulties with coordination and balance, slurred speech and rapid, involuntary eye movements. As the disease progresses, patients are dependent on a wheelchair and their life expectancy is often significantly shortened.

The cause of the disease is a genetic defect that results in the insertion of an expanded polyglutamine tract in the Ataxin-1 protein. The defective protein causes the death of Purkinje cells, the largest neurons of the cerebellum. The underlying mechanisms still remain poorly understood. The loss of the Purkinje cells causes the characteristic symptoms of the disease.

Sabine Liebscher, Smita Saxena and their teams addressed the question of why Purkinje cells selectively degenerate in SCA1 patients, while other neurons are seemingly unaffected. In a mouse model of SCA1, they found that interneurons of the molecular layer, a group of neurons in the cerebellum involved in controlling Purkinje cell activity, are hyperexcitable. They were able to show that this hyperactivity triggers the degeneration of the Purkinje cell. In turn, suppressing the activity of molecular layer interneurons ameliorates disease symptoms and progression.

The results suggest that circuit-level deficits in the cerebellum critically contribute to the development of SCA1. The important role of the molecular layer interneurons in this process was previously unknown. These findings are an important piece of the puzzle towards a better understanding of the disease at the molecular, cellular and circuit level, which is essential for the development of new diagnostic and therapeutic approaches.

Publikation: Pilotto et al.: Early molecular layer interneuron hyperactivity triggers Purkinje neuron degeneration in SCA1, Neuron 2023