Therapeutic prospects for spinocerebellar ataxia type 2 and 3

Abstract

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.

Disturbed calcium signaling in spinocerebellar ataxias and Alzheimer's disease

“…At present, about 30 different genes have been identified which can be the cause of these diseases [1]. In the case of some SCAs, molecular cloning methods revealed the expansion of CAG codons that leads to lengthening of polyglutamine (polyQ) tract in appropriate proteins, such as ataxins for SCA1, SCA2, SCA3 and SCA7 or α1A subunit of P/Q voltage-dependent calcium channel (VDCC) Ca v 2.1 for SCA6 [2].…”

Deranged Calcium Signaling in Purkinje Cells and Pathogenesis in Spinocerebellar Ataxia 2 (SCA2) and Other Ataxias

“…We propose that in Purkinje cells in SCA2 animals and patients, the significant increase in calcium release from the ER into the cytoplasm becomes toxic and initiates cell death via multiple pathways (Fig. 1) [7, 17]. A transient increase in cytoplasmic calcium levels can be tolerated by cells and is important for many neuronal processes but if prolonged can be detrimental.…”

“…Seventeen genes have been associated with these SCAs and it is not understood how mutations in those SCA-associated genes lead to the SCA pathogenesis [5]. The pathogenesis of SCAs is not fully understood, however, several different pathogenic mechanisms have been studied in SCAs such as dysregulation of transcription and gene expression, alterations in calcium homeostasis and synaptic neurotransmission, mitochondrial stress and apoptosis (reviewed in [4, 6, 7]). Currently, therapy for SCA patients is mainly supportive and directed at treating individual symptoms in each [7, 8].…”

Intracellular calcium channels: Inositol-1,4,5-trisphosphate receptors

“…Although there is a phenotypic overlap with cerebellar atrophy and ataxia in all SCA patients, other brain regions may be affected in different type of disease. The pathogenesis of SCAs is not fully understood, however, several different pathogenic mechanisms have been studied in SCAs such as dysregulation of transcription and gene expression, alterations in calcium homeostasis and synaptic neurotransmission, mitochondrial stress and apoptosis (reviewed in (Bezprozvanny and Klockgether, 2010; Carlson et al, 2009; Kasumu and Bezprozvanny, 2012; Matilla-Duenas et al, 2009)).…”