Several neurodegenerative disorders are produced by the abnormal expansion of a glutamine tract in the sequence of proteins specific for each disease. In most cases, the normal function of the vulnerable protein is not known, and it is commonly accepted that the tendency of the mutant version to form protein aggregates, rather than a loss of function, is more directly related to the onset of the pathology. In the case of spinocerebellar ataxia type 6 (SCA6), however, we know that the culprit is the α1A-subunit of the P/Q-type calcium channel, which contains a poly-Q tract in the carboxyl terminus. This raises the possibility that there may be more than aggregate formation to the presence of the poly-Q stretch in SCA6. Indeed, as Restituito et al. report in the September 1 issue of The Journal of Neuroscience , the expression of a mutant α1A-subunit can alter the kinetic properties of channels made from specific subunit combinations.

The authors used Xenopus oocytes to express chimeric α1A-subunits bearing poly-Q tracts of different lengths in combination with different β-subunits. They observed that the presence of a 30-residue poly-Q stretch in the α1A-subunit shifted the activation voltage of the calcium channels to more negative potentials and slowed their inactivation rate. These effects were only seen if the channels included the β4-subunit, which is highly expressed in the Purkinje neurons — the cell type most affected in SCA6.

It remains to be determined whether a similar effect of the mutation can be found on the native subunit combinations found in Purkinje neurons. As Restituito et al. also show in their study, the α1A exon that encodes the poly-Q stretch is expressed at high levels in this cell type, making it entirely possible that the pathological changes in SCA6 may be partly due to the excessive entry of calcium into the Purkinje cells. If SCA6 turns out to be a channelopathy, we would have a new, but familiar, lead to follow in search of a therapy for this disease.