Disturbance of intracellular lipid storage in cell models of several types of spinocerebellar ataxias

[Speaker] Takahiro Seki:1
[Co-author] Mutsumi Oshima:1, Yuki Kurauchi:1, Akinori Hisatsune:2,3, Hiroshi Katsuki:1
1:Department of Chemico-Pharmacological Sciences, Graduate School of Pharmaceutical Sciences, Kumamoto University, Japan, 2:Priority Organization for lnnovation and Excellence, Kumamoto University, Japan, 3:Program for Leading Graduate Schools “HIGO Program”, Kumamoto University, Japan

Spinocerebellar ataxia (SCA) is autosomal-dominantly inherited spinocerebellar degeneration (SCD), a neurodegenerative disease characterized by a progressive cerebellar ataxia. SCA is classified into 46 types (SCA1-46) by the differences in the locus of causal genes. Recently, we have revealed that the expression of missense and nonsense mutations of transmembrane protein 240 (TMEM240), which cause SCA21, significantly decreased lipid droplets (LDs) in HeLa cells. Since LDs contain neutral lipids, SCA21 mutant TMEM240 would disturb intracellular neutral lipid storage. Several causal genes of SCAs are related to lipid biogenesis (ELOVL4 in SCA34 and ELOVL5 in SCA38) and lipid signaling (PKCγ in SCA14, IP3R1 in SC15 and SCA29, PLD3 in SCA46). Therefore, we hypothesized that disturbance of intercellular lipid storage might be involved in the common pathogenesis of SCAs. In the present study, we investigated whether various SCA causal proteins affected the LD accumulation in HeLa cells. We first examined the expression of ELOVL4 and ELOVL5, which participate in the elongation of fatty acids. Although wild-type ELOVL4 and ELOVL5 significantly increased LDs in HeLa cells, the expression of SCA34 mutant ELOVL4 and SCA38 mutant ELOVL5 failed to increase them. On the contrary, SCA14 mutant PKCγ significantly increased LDs, while wild-type PKCγ did not affect them. Finally, we examined the effect of wild-type (Q28) and polyglutamine-expanded (Q84) mutant ATXN3 that causes SCA3. Although ATXN3 has an ability to deubiquitinate polyubiquitin chains, its physiological roles in cellular functions and in lipid signaling or lipid storage remain unknown. The number of LDs did not affected in HeLa cells expressing wild-type ATXN3 and SCA3 mutant ATXN3 without aggregates. However, LDs were significantly decreased in cells with aggregates of mutant ATXN3. Taken together, we revealed that 5 different causal mutant proteins of SCAs disturbed intracellular neutral lipid storage. Purkinje cells are involved in cerebellar functions and are frequently degenerated in patients and model mice of SCAs. Since the highly-branched large dendrites are characteristic of cerebellar Purkinje cells, the disturbance of lipid storage would affect the functions and morphologies of Purkinje cells, leading to the pathogenesis of SCAs.
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