Abstract
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 LC3-II, 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 lithium chronic treatment as a promising strategy for the treatment of Machado-Joseph disease (MJD).
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Apoptosis Regulatory Proteins / metabolism
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Ataxin-3
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Autophagy / drug effects
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Autophagy / physiology
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Autophagy-Related Protein 7
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Beclin-1
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Brain / drug effects
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Brain / physiopathology
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Disease Models, Animal
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Disease Progression
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Exploratory Behavior / drug effects
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Exploratory Behavior / physiology
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Humans
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Lithium Chloride / pharmacology*
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Machado-Joseph Disease / drug therapy*
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Machado-Joseph Disease / physiopathology*
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Male
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Mice, Transgenic
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Microtubule-Associated Proteins / metabolism
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Motor Activity / drug effects*
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Motor Activity / physiology*
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Nerve Tissue Proteins / genetics
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Nerve Tissue Proteins / metabolism
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Neuromuscular Agents / pharmacology*
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Nuclear Proteins / genetics
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Nuclear Proteins / metabolism
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Postural Balance / drug effects
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Postural Balance / physiology
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Repressor Proteins / genetics
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Repressor Proteins / metabolism
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Treatment Outcome
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Tremor / drug therapy
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Tremor / physiopathology
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Weight Loss / drug effects
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Weight Loss / physiology
Substances
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Apoptosis Regulatory Proteins
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Atg7 protein, mouse
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Beclin-1
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Becn1 protein, mouse
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Microtubule-Associated Proteins
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Nerve Tissue Proteins
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Neuromuscular Agents
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Nuclear Proteins
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Repressor Proteins
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ATXN3 protein, human
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Ataxin-3
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Autophagy-Related Protein 7
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Lithium Chloride