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Researchers from the teams of Andrea Németh (NDCN) and Esther Becker (DPAG) have published an important paper reporting dominant mutations that cause a new type of cerebellar ataxia, Spinocerebellar Ataxia type 44.

Nemeth Esther Becker and her lab
Cell-based experiments characterise the function of the mutant receptors

Spinocerebellar ataxias are a group of diseases that are caused by degenerative changes in the cerebellum, a part of the brain important for movement control. There are many different types of spinocerebellar ataxia and each may have unique signs and symptoms. However, in general, all are characterized by problems with movement that tend to get worse over time.

Publishing in the American Journal of Human Genetics, they described a series of mutations in a human gene called GRM1 that produces a glutamate receptor known as mGlur1. mGlur1 is one of the most abundant of its group of receptors in the Central Nervous System and is particularly rich in a group of brain cells in the cerebellum known as Purkinje cells after the man who discovered them. Disease causing mutations in GRM1 are quite rare. However, a single family with recessive mutations has been identified causing cerebellar ataxia and intellectual disability.

This is a really exciting development in understanding both neurodegenerative and neurodevelopmental cerebellar ataxias. GRM1 is at the centre of numerous neuronal pathways, and the identification of possible modulating therapies for GRM1 mutations may also have relevance to other gene mutations. 

- Andrea Nemeth

In the new paper Watson and colleagues identified, for the first time, dominant mutations in GRM1 that cause distinct disease symptoms. Two of the mutations led to increased receptor activity and caused slowly progressive ataxia with disease onset between the ages of 20 and 50. These families did not carry any other known spinocerebellar ataxia-causing mutations. They also identified another mutation occurring in a child, the parents were unaffected, that led to the production of a shorter form of the protein. This caused intellectual disability and cerebellar ataxia without apparent shrinking of the cerebellum.

The finding of mutations that led to increased receptor activity are particularly important because drugs are available that have the opposite effect, reducing activity. The researchers tested an approved mGluR1 drug Nitazoxanide against these mutant receptors in laboratory conditions.  Nitazoxanide was indeed shown to inhibit the mutant receptor in these experiments.  This offers the hope that drugs targeting mGlur1 may one day offer therapeutic opportunities in cerebellar ataxias.  However, much more work needs to be done before we can establish that they will work in humans.