Intracerebellar upregulation of Rheb(S16H) ameliorates motor dysfunction in mice with SCA2

Area of Science:

• Neuroscience
• Genetics
• Molecular Biology

Background:

• Cerebellar ataxia (CA) involves impaired coordination and balance due to cerebellar neuron loss, with limited treatment options.
• Reduced signaling in the mammalian target of rapamycin complex 1 (mTORC1) pathway was observed in the cerebellum of spinocerebellar ataxia type 2 (SCA2) mouse models.

Purpose of the Study:

• To investigate the therapeutic potential of upregulating the mTORC1 pathway via Ras homolog enriched in brain [Rheb(S16H)] in SCA2 mice.
• To determine if enhancing mTORC1 signaling can ameliorate motor dysfunction and neurodegeneration in SCA2.

Main Methods:

• Adeno-associated virus serotype 1 (AAV1) carrying constitutively active Rheb [Rheb(S16H)] was injected intracerebellarly into SCA2 mice.
• Expression of Rheb(S16H) in Purkinje cells and levels of neurotrophic factors were analyzed.
• Behavioral tests and histological assessments were performed to evaluate motor function and neuronal protection.

Main Results:

• Intracerebellar administration of AAV1-Rheb(S16H) successfully increased Rheb(S16H) expression in Purkinje cells.
• Treatment led to elevated levels of neurotrophic factors and significantly reduced abnormal behaviors in SCA2 mice.
• Rheb(S16H) upregulation provided neuroprotection to Purkinje cells, mitigating SCA2-related pathology.

Conclusions:

• Upregulating Rheb(S16H) in the cerebellum effectively activates the mTORC1 pathway.
• This intervention demonstrates therapeutic benefits for motor dysfunction and neuronal loss in a mouse model of hereditary CA.
• Targeting Rheb(S16H) and mTORC1 signaling represents a potential therapeutic strategy for cerebellar ataxias.