Jan 2026· International Journal of Cell Biology· Vol 2026· 0 citations· 82 references
Medicine
TL;DR
It is demonstrated that sodium butyrate (NaB), a histone deacetylase inhibitor and microbial metabolite, ameliorates ALS‐related phenotypes in C. elegans and mammalian cell models expressing mutant isoforms of Sod1 linked to ALS.
Abstract
Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease characterised by motor neuron loss and protein aggregation, commonly driven by mutations in superoxide dismutase 1 (Sod1). Recent evidence implicates gut microbiota–derived metabolites, such as butyrate, in modulating neurodegeneration, but the underlying mechanisms remain unclear. Here, we demonstrate that sodium butyrate (NaB), a histone deacetylase inhibitor and microbial metabolite, ameliorates ALS‐related phenotypes in C. elegans and mammalian cell models expressing mutant isoforms of Sod1 linked to ALS. NaB treatment prevented Sod1 aggregation and restored motor function and axonal integrity in transgenic worms overexpressing Sod1G85R. Mechanistically, NaB recapitulated the effects of the pan‐HDAC inhibitor trichostatin A, suggesting HDAC inhibition as key to reducing Sod1 aggregation and its downstream effects. Application of NaB or the HDAC inhibitor valproic acid also prevented aggregation of Sod1A4V, Sod1G85R or Sod1G37R in transfected human neuroblastoma cells. These findings support a conserved neuroprotective role for NaB and HDAC inhibitors via their antiaggregation activity. Our findings also verify C. elegans and neuroblastoma cell lines as excellent research tools to explore the mechanisms underlying the antiaggregation action of NaB and HDAC inhibitors, as well as their potential for future therapeutic development.
These findings establish NABi as a promising therapeutic candidate for SOD1G93A-associated familial ALS, demonstrating its capacity to selectively target pathological protein conformations while preserving normal cellular function.
Min-Kyung Nam, Y. Oh, Yemi Choi et al.· ACS Chemical Neuroscience· 0 citations
Simple Summary Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease that affects motor neurons, leading to progressive muscle weakness and severe muscle wasting. In addition to neuronal loss, increasing evidence suggests that problems in mitochondrial function, the process by which cells produce energy, may contribute to disease development and progression. In this study, we investigated the effects of Mdivi-1, a drug that inhibits mitochondrial fragmentation, in a mouse model of ALS. Treatment began before symptoms appeared in order to assess whether it could slow disease progression. Our findings showed that Mdivi-1 partially protected motor neurones in the spinal cord, but this did not result in improved motor performance. Moreover, treated animals developed more severe muscle wasting and changes in muscle fiber composition. We also observed cellular alterations associated with impaired neuromuscular function. Overall, these results highlight that mitochondrial dynamics play a complex and context-dependent role in the disease. A better understanding of these mechanisms will be important for developing more effective therapeutic strategies for ALS.
Maria Ciuro, Chantal Rovetto, Angela A. Sirna et al.· Biology· 0 citations
A variant-specific insight is revealed into CMT2A disease mechanisms and HDAC6 is confirmed as a promising target for further therapeutic development by showing that mitochondrial trafficking defects could be alleviated by treatment with an HDAC6 inhibitor.
Lydia H. Jestice, Larissa Butler, Rebecca A. Lea et al.· JCI Insight· 0 citations
Growing evidence suggests that impaired phagocytosis/autophagy and histone deacetylase 3 (HDAC3)‐mediated microglial activation contribute significantly to Alzheimer's disease (AD) pathogenesis by promoting pathological protein aggregation. The ketogenic diet (KD) has demonstrated neuroprotective effects in AD, potentially through modulation of phagocytosis, autophagy, and inflammation. However, the underlying mechanisms remain unclear. Here, we report that a 12‐week KD treatment ameliorated cognitive deficits, reduced amyloid‐β (Aβ) deposition and tau hyperphosphorylation, and attenuated neuroinflammation in male APP/PS1 mice. Mechanistic studies revealed that these effects were associated with the modulation of microglial HDAC3. Specifically, KD downregulated microglial HDAC3, thereby enhancing Aβ phagocytosis, activating AMPK–ULK1‐dependent autophagy, and restraining NLRP3 inflammasome activation, thereby promoting pathologic protein clearance. Given that β‐hydroxybutyrate (BHB) is a major circulating ketone body produced during KD, we tested whether BHB recapitulates these effects in vitro. In Aβ‐induced BV2 microglia, BHB mimicked the neuroprotective effects by downregulating HDAC3, which markedly enhanced Aβ clearance and suppressed inflammatory responses; these neuroprotective effects were largely abrogated by HDAC3 overexpression. To further confirm the causal role of microglial HDAC3 in mediating KD effects, we performed microglia‐specific HDAC3 knockdown via AAV11‐Iba1‐shHDAC3. Notably, this manipulation enhanced both Aβ phagocytosis and autophagic degradation while inhibiting NLRP3 activation and contributed to neuroprotection. Overall, our findings suggest a novel mechanism by which KD exerts neuroprotective effects through modulation of the microglial HDAC3–AMPK–ULK1 axis and highlight microglia‐specific HDAC3 inhibition as a promising therapeutic strategy for AD that simultaneously enhances Aβ clearance and attenuates neuroinflammation.
Mingxiao Zheng, Gabriele Loers, Sheng-Nan Lin et al.· Food Frontiers· 0 citations
Spinal muscular atrophy (SMA) is a severe neuromuscular disorder caused by homozygous deletions or mutations in the SMN1 gene, resulting in reduced levels of the ubiquitously expressed survival motor neuron protein and progressive degeneration of lower motor neurons. Although autophagy dysregulation has been implicated in SMA pathology, the therapeutic benefit of modulating this pathway remains controversial. Here, we screened autophagy modulators in a previously characterized Caenorhabditis elegans SMA model. We identified that pharmacological activation of autophagy, but not inhibition, significantly improved neuromuscular function, as indicated by two independent functional readouts: pharyngeal pumping and locomotor activity assays. These beneficial effects were validated in an independent severe C. elegans SMA mutant allele and were observed in metabolically active and inactive food conditions. Furthermore, autophagy activators significantly extended lifespan of SMA nematodes without affecting controls. Notably, rapamycin and resveratrol increased endogenous SMN-1 protein levels, and improved neuromuscular function was dependent on an intact autophagy pathway. Collectively, our findings support enhancing autophagic activity as a combinatorial treatment strategy for SMA patients.
Unknown authors· ACS Chemical Neuroscience· 0 citations
Findings support the mtFUS zebrafish model as a useful platform for ALS drug discovery and identify tribenzylamine as a candidate modulator of ALS-associated phenotypes, with effects linked to transcriptomic remodeling and neuronally active sex steroid signaling.
Yongbo Seo, Jeonghyeon Lee, Yunkyoung Lee et al.· Biomedicine & pharmacotherap...· 0 citations
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