Reduced cerebellar rhythm by climbing fiber denervation is linked to motor rhythm deficits in mice and ataxia severity in patients.
Journal
Science translational medicine
Journal Volume
17
Journal Issue
787
Start Page
eadk3922
ISSN
1946-6234
Date Issued
2025-02-26
Author(s)
Lin, Chih-Chun
Fang, Ke-Chu
Balbo, Ilaria
Liang, Ting-Yu
Liu, Chia-Wei
Liu, Wen-Chuan
Wang, Yi-Mei
Hung, Yen-Ling
Geng, Scott Kun
Ni, Chun-Lun
Driscoll, Christopher P
Ruff, David S
Kumar, Ami
Amokrane, Nadia
Desai, Natasha
Faust, Phyllis L
Louis, Elan D
Kuo, Sheng-Han
Abstract
Cerebellar ataxia results from various genetic and nongenetic disorders and is characterized by involuntary movements that impair precision and motor rhythm. Here, we report that climbing fiber (CF) denervation is a common pathophysiology underlying motor rhythm loss in cerebellar ataxia. By examining cerebellar pathology in patients with spinocerebellar ataxia (SCA) types 1, 2, and 6 and multiple system atrophy, we identified CF degeneration with synaptic loss as a shared pathophysiology. Optogenetic silencing of CF synaptic activity in mice induced ataxia-like motor dysfunctions and loss of motor precision. In addition, CF silencing resulted in cerebellar and motor rhythm loss, another core feature of ataxia. This rhythm loss was predominantly CF dependent and resistant to Purkinje cell-specific lesioning by diphtheria toxin. Correspondingly, two patients with inferior olive pathology, the brain site that provides CFs to Purkinje cells, presented with ataxia and cerebellar rhythm loss. Patients with genetic or nongenetic cerebellar ataxia exhibited cerebellar rhythm loss that correlated with the Scale for the Assessment and Rating of Ataxia. Chemogenetic stimulation of CFs improved cerebellar and motor rhythms as well as motor performance in the SCA type 1 mouse model of ataxia. These results suggest that CF-dependent cerebellar rhythm loss occurs across different types of cerebellar ataxia, contributing to motor imprecision and motor rhythm loss, two defining features of ataxia.
SDGs
Type
journal article