Antisense Oligonucleotide Therapy Targeted AgainstATXN3Improves Potassium Channel-Mediated Purkinje Neuron Dysfunction in Spinocerebellar Ataxia Type 3

Spinocerebellar ataxia type 3 (SCA3) is the second-most common CAG repeat disease, caused by a glutamine-encoding expansion in the ATXN3 protein. SCA3 is characterized by spinocerebellar degeneration leading to progressive motor incoordination and early death. Previous studies suggest that potassium channel dysfunction underlies early abnormalities in cerebellar cortical Purkinje neuron firing in SCA3. However, cerebellar cortical degeneration is often modest both in the human disease and mouse models of SCA3, raising uncertainty about the role of cerebellar dysfunction in SCA3. Here, we address this question by investigating Purkinje neuron excitability in SCA3. In early-stage SCA3 mice, we confirm a previously identified increase in excitability of cerebellar Purkinje neurons and associate this excitability with reduced transcripts of two voltage-gated potassium (K-V) channels,Kcna6andKcnc3, as well as motor impairment. Intracerebroventricular delivery of antisense oligonucleotides (ASO) to reduce mutant ATXN3 restores normal excitability to SCA3 Purkinje neurons and rescues transcript levels ofKcna6andKcnc3. Interestingly, while an even broader range of K(V)channel transcripts shows reduced levels in late-stage SCA3 mice, cerebellar Purkinje neuron physiology was not further altered despite continued worsening of motor impairment. These results suggest the progressive motor phenotype observed in SCA3 may not reflect ongoing changes in the cerebellar cortex but instead dysfunction of other neuronal structures within and beyond the cerebellum. Nevertheless, the early rescue of both K(V)channel expression and neuronal excitability by ASO treatment suggests that cerebellar cortical dysfunction contributes meaningfully to motor dysfunction in SCA3.

Automated summary

SCA3 is the second most common CAG repeat disease caused by a glutamine-encoding expansion in the ATXN3 protein, leading to degeneration of the spinocerebellum and progressive motor coordination disorders. Studies suggest that early abnormalities in cerebellar cortical Purkinje neuron excitability may underlie SCA3, and intervention can restore neuronal excitability. While a broader range of potassium channel transcripts may be reduced in late-stage SCA3, cerebellar Purkinje neuron physiology remains stable despite worsening motor impairment, indicating dysfunction of other neuronal structures beyond the cerebellum may contribute to the progressive motor phenotype observed in SCA3.