lithium-chloride and Machado-Joseph-Disease

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).

Topics: Animals; Apoptosis Regulatory Proteins; Ataxin-3; Autophagy; Autophagy-Related Protein 7; Beclin-1; Brain; Disease Models, Animal; Disease Progression; Exploratory Behavior; Humans; Lithium Chloride; Machado-Joseph Disease; Male; Mice, Transgenic; Microtubule-Associated Proteins; Motor Activity; Nerve Tissue Proteins; Neuromuscular Agents; Nuclear Proteins; Postural Balance; Repressor Proteins; Treatment Outcome; Tremor; Weight Loss

To investigate the in vivo functions of normal prion protein (PrP) in Drosophila, we utilized characterized transgenic flies expressing ³(F)⁴-tagged mouse PrP (Mo-PrP³(F)⁴). The neurotoxicity of pathogenic Machado-Joseph Disease (MJD) glutamine (Q) 78 and 127Q proteins were enhanced by the co-expression of Mo-PrP³(F)⁴in the fly eyes, while the eyes of controls flies and flies expressing Mo-PrP³(F)⁴) alone or together with MJD-Q27 or 20Q proteins did not show any defect. Susceptibilities to H₂O₂, paraquat, and Dithiothreitol (DTT) were altered in Mo-PrP³(F)⁴ flies. In addition, Mo-PrP³(F)⁴ flies were significantly more susceptible to the perturbation of autophagy signaling by an autophagy inhibitor, 3-methyladenine (3-MA), and inducer, LiCl. Taken together, our data suggest that Mo-PrP³(F)⁴ may enhance the neurotoxicity of pathogenic Poly-Q proteins by perturbing oxidative and autophagy signaling.

Topics: Adenine; Animals; Animals, Genetically Modified; Autophagy; Disease Models, Animal; Dithiothreitol; Drosophila melanogaster; Eye; Lithium Chloride; Machado-Joseph Disease; Mice; Models, Genetic; Neurons; Oxidative Stress; Paraquat; Peptides; Prions; Unfolded Protein Response; Water