Abstract
Spinocerebellar ataxia type 3 (SCA3) is a genetic neurodegenerative disease for which a cure is still needed. Growth hormone (GH) therapy has shown positive effects on the exercise behavior of mice with cerebellar atrophy, retains more Purkinje cells, and exhibits less DNA damage after GH intervention. Insulin-like growth factor 1 (IGF-1) is the downstream mediator of GH that participates in signaling and metabolic regulation for cell growth and modulation pathways, including SCA3-affected pathways. However, the underlying therapeutic mechanisms of GH or IGF-1 in SCA3 are not fully understood. In the present study, tissue-specific genome-scale metabolic network models for SCA3 transgenic mice were proposed based on RNA-seq. An integrative transcriptomic and metabolic network analysis of a SCA3 transgenic mouse model revealed that metabolic signaling pathways were activated to compensate for the metabolic remodeling caused by SCA3 genetic modifications. The effect of IGF-1 intervention on the pathology and balance of SCA3 disease was also explored. IGF-1 has been shown to invoke signaling pathways and improve mitochondrial function and glycolysis pathways to restore cellular functions. As one of the downregulated factors in SCA3 transgenic mice, IGF-1 could be a potential biomarker and therapeutic target.
Highlights
Spinocerebellar ataxia (SCA) is a neurodegenerative genetic disease characterized by common clinical features such as gait instability and affects motor coordination, resulting in alterations in limb control, language, and eye movements
spinocerebellar ataxia type 3 (SCA3) is a polyglutamine neurodegenerative disease resulting from abnormal CAG triplet repeats in the ATXN3 gene (14q21) that lead to the misfolding and accumulation of a pathogenic protein, causing cerebellar dysfunction [1]
Similar trends were observed in t-distributed stochastic neighbor embedding (t-SNE) (Figure 1b), uniform manifold approximation and projection (UMAP) (Figure 1c), and hierarchical clustering analysis (Figure 1d) in transcripts per kilobase million (TPM)
Summary
Spinocerebellar ataxia (SCA) is a neurodegenerative genetic disease characterized by common clinical features such as gait instability and affects motor coordination, resulting in alterations in limb control, language, and eye movements. Other potential therapeutic strategies include neurotransmitter modulators, autophagy enhancers, ion channel inhibitors, growth factors, and stem cell therapies [5]. Among these molecules, neuroprotective molecules, such as growth hormone (GH), insulin-like growth factor-1 (IGF-1), and nerve growth factor, have been tested in SCA3 animal models and in humans through clinical trials and have displayed potential therapeutic effects in patients with SCA3 [6,7]
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