Lithium is one of the oldest psychiatric drugs and still used routinely to ameliorate the symptoms of mood disorders. New results by Huda Zoghbi (Baylor College of Medicine and Howard Hughes Medical Institute), Harry Orr (University of Minnesota) and colleagues now suggest that lithium also holds promise in treating a group of devastating neurodegenerative disorders for which no other treatments exist at present. As the researchers have reported, dietary lithium markedly improved the symptoms in a mouse model of spinocerebellar ataxia.
Spinocerebellar ataxia type 1 (SCA1) is part of a group of inherited, incurable neurodegenerative disease called "triplet repeat diseases". These diseases kill patients (who are typically diagnosed in their thirties and forties) within a few years of disease onset. The name refers to the underlying genetic abnormality: Information for making proteins is stored in DNA as groups of three nucleotides (codons), each specifying a different amino acid (the building blocks of proteins). In triplet repeat diseases, patients inherit a mutant gene containing abnormally long stretches of repeated codons.
In SCA1, the repeated codon is CAG, which specifies glutamine, and patients have an abnormal glutamine stretch in the Ataxin1 protein. This stretch causes Ataxin1 to accumulate and to have altered protein interactions that are toxic to a group of cerebellar neurons called Purkinje cells (which normally coordinate movement) and hippoca mpal neurons (which are important for memory). Patients gradually lose movement control, have impaired cognitive function, and eventually die from the disease because other neurons in the brain stem also degenerate.
The researchers bred mice carrying a mutant gene for Ataxin1 containing a very long CAG repeat (Sca1154Q/2Q mice) which resemble human patients in symptoms and disease progression. After weaning, the mice were fed normal food or food supplemented with lithium for several weeks before assessing their ability to coordinate their movements and testing their cognitive skills. Dietary lithium (given before or after symptoms appeared) improved both coordination and learning and memory in the mutantmice. Lithium did not change the overall appearance of the brain in the Sca1154Q/2Q mice, but it did partly reverse hippocampal neuron degeneration in these animals.
Lithium did not improve the lifespan of the Sac1154Q/2Q mice either (although this could be because the mutant SCA1 protein has some deleterious effects outside the brain). Lithium alone is thus unlikely to be a miracle cure for spinocerebellar ataxia, but the research suggests that is might be of some help to patients who currently have no other treatments available, even if (as is usual), their condition is not diagnosed until the disease is quite advanced.
Given that lithium is in clinical use, the work by Zoghbi and colleagues is expected to quickly lead to clinical trials which will examine whether lithium does indeed have beneficial effects in human patients with spinocerebellar ataxia and related diseases.
Citation: Watase K, Gatchel JR, Sun Y, Emamian E, Atkinson R, et al. (2007) Lithium therapy improves neurological function and hippocampal dendritic arborization in a spinocerebellar ataxia type 1 mouse model. PLoS Med 4(5): e182. (http://medicine.plosjournals.org/perlserv/?request=get-document&doi=10.1371/journal.pmed.0040182)
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