Antisense Oligonucleotide Therapy Targeted Against ATXN3 Improves Potassium Channel–Mediated Purkinje Neuron Dysfunction in Spinocerebellar Ataxia Type 3

David D. Bushart, Annie J. Zalon, Hongjiu Zhang, Logan M. Morrison, Yuanfang Guan, Henry L. Paulson, Vikram G. Shakkottai, Hayley S. McLoughlin

Research output: Contribution to journalArticlepeer-review

Abstract

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 (KV) channels, Kcna6 and Kcnc3, 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 of Kcna6 and Kcnc3. Interestingly, while an even broader range of KV 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 KV channel expression and neuronal excitability by ASO treatment suggests that cerebellar cortical dysfunction contributes meaningfully to motor dysfunction in SCA3.

Original languageEnglish (US)
Pages (from-to)41-53
Number of pages13
JournalCerebellum
Volume20
Issue number1
DOIs
StatePublished - Feb 2021
Externally publishedYes

Keywords

  • Antisense oligonucleotide
  • Ataxia
  • Cerebellum
  • Potassium channel
  • Purkinje neuron

ASJC Scopus subject areas

  • Neurology
  • Clinical Neurology

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