Treadmill training increases the motor activity and neuron survival of the cerebellum in a mouse model of spinocerebellar ataxia type 1

Abstract

Spinocerebellar ataxia (SCA) type 1 (SCA1) is a rare autosomal dominant disorder that is characterized by worsening of disordered coordination, ataxia of the trunk, and other neurological symptoms. Physical activity improves both mobility and the daily living activities of patients with SCA. Intervention with daily regular treadmill exercise may slow the deterioration of cerebellar neurons in SCA1. Therefore, the signal changes and performance of cerebellar neurons after exercise in SCA1 was investigated in this study.We employed a transgenic mouse model of SCA1, generated by amplifying the cytosineadenine-guanine trinucleotide repeat expansions, and the mice underwent 1 month of moderate daily treadmill exercise for 1 hour. The rotarod test revealed that the motor function of the SCA1 mice that underwent training was superior to that of the control SCA1 mice, which did not undergo training. Moreover, the cerebellar pathology revealed preserved Purkinje neurons stained by carbindin with an increase of the neuronal Per Arnt Sim domain protein 4, a key regulation in the structural and functional plasticity of neurons, in the excised SCA1 mice relative to the controls. The mechanism was related to an increase of phosphorylation of ribosomal protein S6, a downstream target of the mammalian target of rapamycin pathway, but not to autophagy activation. This study determined that regular treadmill exercise may play a crucial role in the viable support of cerebellar neurons in SCA1. K E Y W O R D S neuronal Per Arnt Sim domain protein 4, Purkinje neurons, ribosomal protein S6, Spinocerebellar ataxia type 1, treadmill training

Region‐specific preservation of Purkinje cell morphology and motor behavior in the ATXN1[82Q] mouse model of spinocerebellar ataxia 1

“…In the anterior vermis characterized by three thin stripes of AldoC-positive Purkinje cells (25), these stripes are unreliably present in ATXN1[82Q] mice. We also compared AldoC expression with an additional marker of Purkinje cell pathology, i.e., nuclear inclusions that represent a mid-late hallmark in ATXN1[82Q] Purkinje cells (43). To label nuclear inclusions, we stained for p62/SQSTM1 (p62 hereafter), an autophagy adaptor protein that is present at high levels in many neuronal inclusions, including intranuclear inclusions of SCA1 patients (44).…”

Molecular and microstructural biomarkers of neuroplasticity in neurodegenerative disorders through preclinical and diffusion magnetic resonance imaging studies

“…In this scenario, identifying mutations related to several hereditary ataxias has led to developing a growing number of valuable animal models (Manto and Marmolino, 2009). As an example, the study of NP in models of spinocerebellar ataxia (SCA) type 1 (SCA1) concluded that external factors (like regular treadmill exercise) changed vital regulatory pathways in the structural and functional plasticity of the neuron, play a critical role in the viable support of SCA1 mice cerebellar neurons (Chuang et al, 2019). More important, (due to overlapping mechanisms across different NDDs) such mutations could have common molecular pathways by genetically conserved NP mechanisms, amenable to be potentially repaired using the proper molecular tools.…”

Restoration of BDNF-TrkB signaling rescues deficits in a mouse model of SCA6

“…Exercise has been shown to rescue deficits in an SCA1 mouse model 28,29 and in ataxic Snf2h-null mice 30 , although BDNF has not been identified as the mechanism underlying its therapeutic action in these models. We wondered whether exercise, perhaps via elevation of cerebellar BDNF levels, would rescue motor behavioural deficits in SCA6 84Q/84Q mice.…”