Tetramethylpyrazine Nitrone Improves R6/1 Pathology by Restoring Mitochondrial Function and Clearing Mutant Huntingtin

摘要

Huntington's disease(HD) is a neurodegenerative disorder caused by a mutation in the huntingtin gene, resulting in the expression of a misfolded mutant huntingtin protein(mHTT). The cerebral accumulation of mHTT contributes to mitochondrial impairment, synaptic dysfunction, and degeneration of striatal neurons, and is frequently associated with choreiform motor manifestations in affected individuals. Current therapeutic approaches for HD remain predominantly symptomatic, and no curative interventions are currently available for this disease. Tetramethylpyrazine Nitrone(TBN), a novel tetramethylpyrazine derivative functionalized with a nitrone moiety, promotes mitochondrial biogenesis and enhances metabolic function via activation of the PGC-1α(peroxisome proliferator-activated receptor γ coactivator 1α) pathway. This innovative compound has demonstrated neuroprotective efficacy across a range of neurodegenerative disease models, including those of Parkinson's disease, Alzheimer's disease, and amyotrophic lateral sclerosis(ALS). TBN has completed Phase II clinical trials in China for acute ischemic stroke, as well as Phase II investigational studies for ALS, consistently exhibiting a favorable safety profile, excellent tolerability, and encouraging trends toward clinical efficacy. In light of these findings, we sought to evaluate the therapeutic potential and mechanistic foundations of TBN in the context of HD. In R6/1 transgenic HD mice, administration of TBN ameliorated motor deficits and conferred a significant extension in survival. Furthermore, TBN administration attenuated muscular atrophy and fibrosis in the gastrocnemius muscle. Notably, TBN treatment yielded substantial improvements in key neuropathological indicators, including the preservation of striatal medium spiny neurons, suppression of glial activation, and recovery of synaptic integrity. Transcriptomic analysis further indicated that TBN attenuates mHTT aggregation through regulation of Ube2n(Ubiquitin-Conjugating Enzyme E2N). Of particular significance, we elucidated a direct molecular interaction between TBN and PGC-1α, resulting in enhanced mitochondrial performance, thereby implicating PGC-1α activation as a fundamental mechanism underpinning the therapeutic effects of TBN. In summary, TBN mitigates HD progression by counteracting neuropathological changes, promoting mHTT clearance, and restoring mitochondrial function, supporting its further investigation as a promising HD therapeutic candidate.

关键词

Huntington / mitochondrial / ubiquitin / Ube2n / PGC-1α