Abstract
Although the effects of growth hormone (GH) therapy on spinocerebellar ataxia type 3 (SCA3) have been examined in transgenic SCA3 mice, it still poses a nonnegligible risk of cancer when used for a long term. This study investigated the efficacy of IGF-1, a downstream mediator of GH, in vivo for SCA3 treatment. IGF-1 (50 mg/kg) or saline, once a week, was intraperitoneally injected to SCA3 84Q transgenic mice harboring a human ATXN3 gene with a pathogenic expanded 84 cytosine–adenine–guanine (CAG) repeat motif at 9 months of age. Compared with the control mice harboring a 15 CAG repeat motif, the SCA3 84Q mice treated with IGF-1 for 9 months exhibited the improvement only in locomotor function and minimized degeneration of the cerebellar cortex as indicated by the survival of more Purkinje cells with a more favorable mitochondrial function along with a decrease in oxidative stress caused by DNA damage. These findings could be attributable to the inhibition of mitochondrial fission, resulting in mitochondrial fusion, and decreased immunofluorescence staining in aggresome formation and ataxin-3 mutant protein levels, possibly through the enhancement of autophagy. The findings of this study show the therapeutic potential effect of IGF-1 injection for SCA3 to prevent the exacerbation of disease progress.
Highlights
Spinocerebellar ataxia (SCA) is one of the most common genetic neurodegenerative diseases with multiple types
84Q mice displayed a shorter time of latency to fall than did the SCA type 3 (SCA3) 15Q and IGF-1treated SCA3 84Q mice (Figure 1a)
After normalization to the pretreatment point, the percentage of relative latency to fall in the insulin-like growth factor 1 (IGF-1)-treated SCA3 84Q mice was still higher than that in the salineBiomedicines 2022, 10, x FOR PEER
Summary
Spinocerebellar ataxia (SCA) is one of the most common genetic neurodegenerative diseases with multiple types. Compared with patients with SCA1 and SCA2, those with SCA3 have a later onset and present with cerebellar ataxia, peripheral neuropathy, distal muscle atrophy, and hyporeflexia [2]. These symptoms continue to worsen with time, and no known effective treatment is currently available. PolyQ diseases, including SCA, spinal and bulbar muscular atrophy (SBMA), and Huntington’s disease (HD), are currently identified as a group of neurodegenerative disorders [5]. Aggregation and toxicity caused by mutant ataxin-3 are the hallmarks of SCA3 [8]. The clearance of mutant ataxin-3 proteins is proposed as a promising therapeutic strategy [9]
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