Related Experiment Video
Updated: May 24, 2025
Treating SCA1 Mice with Water-Soluble Compounds to Non-Specifically Boost Mitochondrial Function
Published on: January 22, 2017
Intracerebellar upregulation of Rheb(S16H) ameliorates motor dysfunction in mice with SCA2
Sehwan Kim1,2, Junwoo Park1, Hyemi Eo1
1School of Life Science and Biotechnology, BK21 FOUR KNU Creative BioResearch Group, Kyungpook National University, Daegu, 41566, Republic of Korea.
Abstract:
Cerebellar ataxia (CA) is characterized by impaired balance and coordination due to the loss of cerebellar neurons caused by various factors, and effective treatments are currently lacking. Recently, we observed reduced expression of signaling molecules in the mammalian target of rapamycin complex 1 (mTORC1) pathway in the cerebellum of mice with spinocerebellar ataxia type 2 (SCA2) compared with wild-type mice. To investigate the effects of mTORC1 upregulation on motor dysfunction in mice with SCA2, we administered an intracerebellar injection of adeno-associated virus serotype 1 carrying a constitutively active form of Ras homolog enriched in brain [Rheb(S16H)], which is an upstream activator of mTORC1. This treatment led to increased Rheb(S16H) expression in calbindin-D28K-positive Purkinje cells and increased levels of neurotrophic factors. Additionally, Rheb(S16H) upregulation reduced abnormal behaviors and protected Purkinje cells in mice with SCA2. Our findings suggest that upregulating Rheb(S16H) in the cerebellum may be a promising therapeutic strategy for hereditary CA.
Insights
Upregulating the Ras homolog enriched in brain (Rheb) protein in the cerebellum shows promise for treating cerebellar ataxia (CA). This approach improved motor function and protected neurons in a mouse model of spinocerebellar ataxia type 2 (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.
