Lithium Chloride Therapy Fails to Improve Motor Function in a Transgenic Mouse Model of Machado-Joseph Disease

作者：Duarte Silva Sara; Neves Carvalho Andreia; Soares Cunha Carina; Teixeira Castro Andreia; Oliveira Pedro; Silva Fernandes Anabela; Maciel Patricia^*

来源：Cerebellum, 2014, 13(6): 713-727.

DOI：10.1007/s12311-014-0589-9

• Polyglutamine
• Spinocerebellar ataxia
• Lithium
• Autophagy
• Therapy
• Triplet repeats

The accumulation of misfolded proteins in neurons, leading to the formation of cytoplasmic and nuclear aggregates, is a common theme in age-related neurodegenerative diseases, possibly due to disturbances of the proteostasis and insufficient activity of cellular protein clearance pathways. Lithium is a well-known autophagy inducer that exerts neuroprotective effects in different conditions and has been proposed as a promising therapeutic agent for several neurodegenerative diseases. We tested the efficacy of chronic lithium 10.4 mg/kg) treatment in a transgenic mouse model of Machado-Joseph disease, an inherited neurodegenerative disease, caused by an expansion of a polyglutamine tract within the protein ataxin-3. A battery of behavioral tests was used to assess disease progression. In spite of activating autophagy, as suggested by the increased levels of Beclin-1, Atg7, and LC3II, and a reduction in the p62 protein levels, lithium administration showed no overall beneficial effects in this model concerning motor performance, showing a positive impact only in the reduction of tremors at 24 weeks of age. Our results do not support lithiumchronic treatment as a promising strategy for the treatment of Machado-Joseph disease (MJD).

• 出版日期2014-12