Therapeutic prospects for spinocerebellar ataxia type 2 and 3

Spinocerebellar ataxia type 2 (SCA2) and type 3 (SCA3) are autosomal-dominant neurodegenerative disorders. SCA2 primarily affects cerebellar Purkinje neurons. SCA3 primarily affects dentate and pontine nuclei and substantia nigra. Both disorders belong to a class of polyglutamine (polyQ) expansion disorders. SCA2 is caused by a polyQ expansion in the amino-terminal region of a cytosolic protein ataxin-2 (Atxn2). SCA3 is caused by a polyQ expansion in the carboxy-terminal portion of a cytosolic protein ataxin-3 (Atxn3). Both disorders are found worldwide, but SCA2 is common among people of Cuban decent and SCA3 is common among people of Portuguese decent. No effective treatment exist for SCA2, SCA3 or any other polyQ-expansion disorder. Based on anecdotal evidence, a number of small scale clinical trials have been attempted previously for SCA2 and SCA3. These trials were underpowered and did not yield any promising results so far. A number of pathogenic mechanisms have been proposed to explain neuronal dysfunction and degeneration in SCA2 and SCA3. Knockdown of mutant Atxn2 and Atxn3 protein by RNAi or similar approach is most promising avenue of therapeutic development in the long term, but translation of this approach to clinic faces very serious technical challenges. Recent preclinical studies in SCA2 and SCA3 genetic mouse model suggested that abnormal neuronal calcium (Ca²⁺) signaling may play an important role in SCA2 and SCA3 pathology. These studies also suggested that dantrolene and other Ca²⁺ signaling inhibitors and stabilizers may have a therapeutic value for treatment of SCA2 and SCA3. Controlled clinical evaluation of dantrolene, memantine, riluzole, dihydropyridines, CoQ10, creatine or other Ca²⁺ blockers and stabilizers in SCA2 and SCA3 patients is necessary to test clinical importance of these ideas. The EUROSCA consortium provides a potential framework for such clinical evaluation.