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 6

HCY suppresses histone lactylation through AARS1.

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HCY suppresses histone lactylation through AARS1. (A) Comparative immuno...
(A) Comparative immunoblot of pan-histone lactylation in HdhQ111 versus HdhQ7 cells (n = 4). (B) Pan-histone lactylation in striatal tissues from 6-month-old WT and YAC128 mice (n = 6–8). (C) Pan-histone lactylation in SHMT2-knockdown HdhQ7 cells compared with control (n = 3). (D) Analysis of pan-histone lactylation and H3K18la in control and SHMT2-knockdown mouse striatum (n = 3). (E) Pan-histone lactylation in HdhQ7 cells treated with vehicle or SHIN1 (10 μM) for 48 hours (n = 3). (F) Pan-histone lactylation levels in HdhQ7 cells treated with or without HCY (500 μM) for 48 hours (n = 3). (G) Pan-histone lactylation in striatal tissues from 6-month-old WT and YAC128 mice injected with AAV-Con or AAV-SHMT2 (n = 3). (H) Folate supplementation (100 μM, 48 hours) partially restores pan-histone lactylation in HdhQ111 cells (n = 3). (I) Scatter plot of candidate HCY-binding proteins identified by LiP-MS analysis. (J) Histone lactylation in AARS1-knockdown or control HdhQ7 cells treated with or without HCY (500 μM, 48 hours) (n = 3). (K) Pan-histone lactylation in control and AARS1-knockdown HdhQ7 cells treated with or without SHIN1 (10 μM, 48 hours) (n = 3). (L) Histone lactylation in HdhQ7 and HdhQ111 cells transfected with Flag-AARS1 or empty vector (n = 3). (M) Molecular docking showing HCY binding to human AARS1 (PDB: 4XEM) at the predicted lactate binding site. (N) Microscale thermophoresis (MST) analysis of AARS1-HCY interaction using gradient HCY; representative MST curves are shown. (O) MST analysis of AARS1 with or without HCY in the presence of gradient sodium lactate; representative MST curves shown. Data are shown as the mean ± SEM. Unpaired t test was used for A, B, and D–F; 1-way ANOVA with Tukey’s test was used for C, G, H, and J–L. *P < 0.05, **P < 0.01, ***P < 0.001, ****P < 0.0001.