The common pathology of various cerebellar ataxias converges to excessive regression of CFs, which leads to loss of cerebellar rhythms and thus arrhythmic movements, a core feature to define ataxia. Enhancing CF activity chemogenetically can partially reverse the rhythm abnormality, leading to improved motor behaviors.
Cerebellar ataxias are a group of genetic and non-genetic disorders that currently have no effective treatment. Despite their different causes, all forms of ataxia share a common set of motor impairments—specifically, a loss of motor rhythm and precision.
In a recent work, Dr. Ming-Kai Pan in National Taiwan University College of Medicine and Dr. Sheng-Han Kuo in Columbia University have identified a shared pathological feature across various types of ataxia, including spinocerebellar ataxia (SCA) types 1, 2, and 6, Dentatorubral-pallidoluysian atrophy (DRPLA), and the cerebellar type of multiple system atrophy (MSA-C). This pathology involves the regression of cerebellar climbing fibers (CFs), a key neural structure crucial for motor coordination.
More importantly, the severity of ataxia in patients correlates with a loss of cerebellar rhythm, which can be measured using cerebellar electroencephalography (EEG). Further investigations in ataxia mouse models confirmed that CF degeneration leads to disruptions in cerebellar frequency, ultimately causing deficits in motor rhythm and precision—hallmarks of ataxia.
In a proof-of-concept therapy, Dr. Pan and collaborators demonstrated that chemogenetic manipulation can enhance the activity of remaining CFs, leading to significant improvements in both motor rhythm and motor performance in ataxic mice. These findings offer a promising new therapeutic strategy for cerebellar ataxia by targeting a shared underlying pathophysiology across different disease causes.
"Previously, research on cerebellar ataxias has primarily focused on the loss of cerebellar Purkinje cells. However, by the time cell loss occurs, therapeutic interventions are often ineffective or come too late. Our discovery of climbing fiber-dependent mechanisms and cerebellar rhythm disruption presents a novel therapeutic target. More importantly, this mechanism is not limited to a specific type of ataxia but extends across ataxias of various etiologies," said Prof. Ming-Kai Pan.
This work has been published in a world-leading journal, Science Translational Medicine, in Feb, 2025 as a Featured article: “Reduced cerebellar rhythm by climbing fiber denervation is linked to motor rhythm deficits in mice and ataxia severity in patients”. (doi: 10.1126/scitranslmed.adk3922)
Prof. Ming-Kai Pan’s email address: [email protected]
