SHMT2 deficiency disrupts transcriptional regulation through homocysteine-mediated suppression of histone lactylation in Huntington’s disease models
Mingqin Lu, Kexin Li, Shanshan Wu, Zhilong Zheng, Xinyue Li, Shengda Wang, Hanwen Yu, Chunyue Liu, Yueqing Jiang, Xueqin Song, Yan Liu, Xing Guo
Mingqin Lu, Kexin Li, Shanshan Wu, Zhilong Zheng, Xinyue Li, Shengda Wang, Hanwen Yu, Chunyue Liu, Yueqing Jiang, Xueqin Song, Yan Liu, Xing Guo
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Research Article Aging Cell biology Neuroscience

SHMT2 deficiency disrupts transcriptional regulation through homocysteine-mediated suppression of histone lactylation in Huntington’s disease models

Abstract

Huntington’s disease (HD) is a fatal neurodegenerative disorder characterized by progressive motor dysfunction, cognitive decline, and striatal neuron degeneration, primarily affecting medium spiny neurons (MSNs). Despite extensive research, the underlying metabolic vulnerabilities contributing to HD pathogenesis remain poorly understood. In this study, we employed RNA-seq and metabolomics analyses to identify marked dysregulation of 1-carbon metabolism in HD. We validated that SHMT2, a key mitochondrial enzyme in the mitochondrial 1-carbon pathway, was substantially downregulated in HD patient–derived iPSC-differentiated human striatal organoids (hSOs) and YAC128 mice. Functionally, pharmacologic inhibition or genetic deletion of SHMT2 exacerbated mutant huntingtin aggregation, induced MSN degeneration in hSOs, and impaired motor function in WT mice. Conversely, SHMT2 overexpression attenuated MSN degeneration in HD-hSOs and improved motor performance in YAC128 mice. Mechanistically, SHMT2 deficiency led to accumulation of homocysteine, which interacted with AARS1 and suppressed histone lactylation, thereby perturbing transcriptional regulation and associating with neurodegenerative phenotypes. Finally, we demonstrated that the HD clinical drug haloperidol modulated SHMT2 expression and restored histone lactylation, providing a pharmacologic tool to probe SHMT2-dependent metabolic and epigenetic regulation in HD models. These findings highlight a metabolic-epigenetic axis as a promising therapeutic target for HD.

Authors

Mingqin Lu, Kexin Li, Shanshan Wu, Zhilong Zheng, Xinyue Li, Shengda Wang, Hanwen Yu, Chunyue Liu, Yueqing Jiang, Xueqin Song, Yan Liu, Xing Guo

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Figure 4

SHMT2 overexpression ameliorates neurodegeneration both in vivo and in vitro.

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SHMT2 overexpression ameliorates neurodegeneration both in vivo and in v...
(A) Schematic of lentiviral SHMT2 overexpression in control and HD iPSCs and subsequent hSO differentiation; SHMT2 protein confirmed by Western blot. (B) Neuronal complexity in control hSOs (con-hSOs) and HD-hSOs with or without SHMT2 overexpression, quantified by Sholl analysis (scale bar: 20 μm; n = 60). (C) DARPP-32 and GFP costaining in con-hSOs and HD-hSOs with or without SHMT2 overexpression at D60 (scale bar: 20 μm; n = 3). (D) Nuclear fragmentation in control and SHMT2-overexpressing con-hSOs and HD-hSOs at D60 (scale bar: 10 μm; n = 3). (E) Timeline of AAV-Con and AAV-SHMT2 stereotaxic injections into the striatum of 4-month-old WT and YAC128 mice. (F) Volcano plot illustrating differential gene expression in striatal tissue from YAC128 mice with or without SHMT2 overexpression. DEG cutoff: |log2FC| ≥ 0.25, Padj ≤ 0.05. (G) GO Biological Process enrichment of DEGs from YAC128 mice with or without SHMT2 overexpression. (H) DARPP-32 protein in the striatum of WT and YAC128 mice following AAV-Con or AAV-SHMT2 injection (n = 3). (I) GFAP and GFP staining in the striatum of WT and YAC128 mice after AAV-SHMT2 overexpression (n = 3; scale bar: 20 μm). (J) mHTT immunoreactivity in striatal sections from WT and YAC128 mice with or without AAV-SHMT2 overexpression (n = 3; scale bar: 20 μm). (K–M) Behavioral assessments 2 months after AAV-Con or AAV-SHMT2 injection (n = 14–15). Tests included (K) rotarod test, (L) balance beam test, and (M) open-field test. Data are shown as the mean ± SEM. Two-way ANOVA with Šídák’s test was used for B; 1-way ANOVA with Tukey’s test was used for C, D, and H–M. *P < 0.05, **P < 0.01, ***P < 0.001, ****P < 0.0001.