Fig. 4.

Strategies for SCA2 therapeutic development. (a) Antisense oligonucleotide (ASO) therapy. The oligonucleotide sequence complementary to a target mRNA is used to prevent the translation of the ataxin-2 mutant (Atxn2^mut) protein. (b) Stem cell therapy. Mesenchymal stem cells are extracted from healthy donors and intravenously administrated into SCA patients. Stem cells act as immunomodulators and neuroprotectors and regenerate affected neurons in SCA patients. (c) Calcium stabilizers, such as ryanodine, dantrolene, riluzole, inositol-1,4,5-trisphosphate-5-phosphatase (5PP), NS13001, and chlorzoxazone (CHZ), normalize calcium signaling disturbed in SCA2 cerebellar Purkinje cells (PCs), improving PC firing and morphology and ameliorating motor performance of SCA2 mice. (d) Prevention of mutant ataxin-2 aggregation can be achieved by the polyQ-binding proteins such as polyQ-binding protein 1 (QBP1) or huntingtin polyQ-binding peptoid 09 (HQP09) that inhibit polyQ aggregation. Another way to suppress mutant ataxin-2 aggregation is the overexpression of the co-chaperone/E3 ligase C-terminal constitutive Hsp70 (Hsc70)-interacting protein (CHIP) that links the protein folding machinery with the ubiquitin–proteasome system (UPS) and lead to the mutant ataxin-2 degradation in the proteasome. Molecular chaperones such as heat shock protein (HSP) 70 kDa (Hsp70) and heat shock transcription factor (HSF1) that regulates the expression of the HSPs also provoke significant suppression of aggregation formation