Abstract
Spinocerebellar ataxia type 3 (SCA3), a hereditary and lethal neurodegenerative disease, is attributed to the abnormal accumulation of undegradable polyglutamine (polyQ), which is encoded by mutated ataxin-3 gene (ATXN3). The toxic fragments processed from mutant ATXN3 can induce neuronal death, leading to the muscular incoordination of the human body. Some treatment strategies of SCA3 are preferentially focused on depleting the abnormal aggregates, which led to the discovery of small molecule n-butylidenephthalide (n-BP). n-BP-promoted autophagy protected the loss of Purkinje cell in the cerebellum that regulates the network associated with motor functions. We report that the n-BP treatment may be effective in treating SCA3 disease. n-BP treatment led to the depletion of mutant ATXN3 with the expanded polyQ chain and the toxic fragments resulting in increased metabolic activity and alleviated atrophy of SCA3 murine cerebellum. Furthermore, n-BP treated animal and HEK-293GFP-ATXN3-84Q cell models could consistently show the depletion of aggregates through mTOR inhibition. With its unique mechanism, the two autophagic inhibitors Bafilomycin A1 and wortmannin could halt the n-BP-induced elimination of aggregates. Collectively, n-BP shows promising results for the treatment of SCA3.
Highlights
Polyglutamine diseases are a group of genetic neurodegeneration caused by the excess of cytosine-adenine-guanine (CAG) repeats that encode a long polyQ tract in the translated proteins [1,2,3,4,5,6]
These findings indicate that more Purkinje cells were protected from loss upon n-BP administration compared to spinocerebellar ataxias (SCAs) type 3 (SCA3) and SCA3-V groups
Cemal et al described that SCA3 (MJD84.2) mice from 20 weeks of age tended to lose weight and progressed with a defect in coordination and limb weakness [49]
Summary
Polyglutamine (polyQ) diseases are a group of genetic neurodegeneration caused by the excess of cytosine-adenine-guanine (CAG) repeats that encode a long polyQ tract in the translated proteins [1,2,3,4,5,6]. ATXN3 is involved in the editing of poly-ubiquitin chains to regulate protein degradation as a function of deubiquitinating enzyme [20,21] and is associated with cytoskeletal formation [22], dendritic differentiation [9], cell apoptosis, and protection against polyQ proteins in vivo [23]. These functions are attributed to the unique structure of the protein that is composed of Josephin domain with the capability of deubiquitination at the N terminus and the C terminal portion containing ubiquitininteracting motifs (UIM) and polyQ regions [24,25]. SCA3 disease through the mTOR inhibition to promote autophagy, thereby protecting the cerebellar Purkinje cells
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