THERAPEUTIC PROSPECTS FOR SPINOCEREBELLAR ATAXIA TYPE 2 AND 3

摘要

Spinocerebellar ataxia type 2 (SCA2) and type 3 (SCA3) are autoso-mal-dominant neurodegenerative disorders. SCA2 primarily affects cerebellar Purkinje neurons and SCA3 primarily affects dentate and pontine nuclei and the 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 the cytosolic protein ataxin-2 (ATXN2) and SCA3 is caused by a polyQ expansion in the car-boxy-terminal portion of ataxin-3 (ATXN3). Both disorders are found worldwide, but SCA2 is more common among people of Cuban descent and SCA3 is more common among people of Portuguese descent. No effective treatment exists 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 promising results. A number of pathogenetic mechanisms have been proposed to explain the neuronal dysfunction and degeneration in SCA2 and SCA3. Knockdown of mutant ATXN2 and ATXN3 protein by RNAi or a similar approach is the most promising avenue of therapeutic development in the long term, but translation of this approach to the clinic faces very serious technical challenges. Recent preclinical studies in SCA2 and SCA3 genetic mouse models suggested that abnormal neuronal calcium (Ca~2+) signaling may play an important role in SCA2 and SCA3 pathology. These studies also suggested that dantrolene and other Ca~2+ signaling inhibitors and stabilizers may have therapeutic value for the treatment of SCA2 and SCA3. Controlled clinical evaluation ofdantrolene, memantine, riluzole, dihydropyridines, CoQIO, creatine or other Ca~2+ blockers and stabilizers in SCA2 and SCA3 patients is necessary to test the clinical importance of this approach. The EUROSCA consortium provides a potential framework for such clinical evaluation.