The vitamin C derivative sodium L-ascorbyl-2-phosphate attenuates mutant huntingtin pathology and neuroinflammation in Huntington's disease models

Huntington’s disease (HD) is a fatal, autosomal-dominant neurodegenerative disorder caused by CAG-repeat expansion in the huntingtin (HTT) gene, leading to accumulation of mutant huntingtin (mHTT) aggregates and progressive neuronal dysfunction. Although extensive efforts have been made, no effective disease-modifying therapy currently exists. We investigated the therapeutic potential of sodium L-ascorbyl-2-phosphate (AA2P), a stable vitamin C derivative, across complementary HD models. Using transient HTT-N171-150Q and full-length HTT-120Q 293T cells, macaque primary cortical neurons, and HD knock-in (KI-140Q) mice, we evaluated AA2P effects through integrated molecular, histological, motor, positron-emission tomography (PET), and RNA sequencing (RNA-seq) analyses. AA2P reduced expanded-polyglutamine (polyQ) HTT in 293T cells, preserved neurite architecture in macaque primary neurons, and reduced mEM48- and 1C2-reactive HTT signals in HD KI-140Q mouse striatum. Oral treatment improved selected motor outcomes, reduced 18-kDa translocator protein (TSPO)- and ionized calcium-binding adaptor molecule 1 (Iba1)-associated neuroinflammatory signals, and partially shifted striatal transcriptional programs toward wild type. Changes in sequestosome 1 (p62/SQSTM1), microtubule-associated protein 1 light chain 3 (LC3), and Beclin-1 accompanied AA2P treatment but did not establish increased autophagic flux or a causal role for autophagy. Collectively, our findings support further investigation of AA2P as a stable and accessible candidate for HD. By reducing mHTT pathology and coordinating neuronal, inflammatory, and proteostasis-associated responses across complementary models, AA2P warrants further translational and causal evaluation.