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 3

SHMT2 deficiency induces neurodegeneration and motor dysfunction in vivo.

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SHMT2 deficiency induces neurodegeneration and motor dysfunction in vivo...
(A) Schematic timeline of stereotaxic injections of AAV-shScr or AAV-shSHMT2 into the striatum of 2-month-old mice, followed by behavioral and pathological analyses at indicated time points. (B) SHMT2 and DARPP-32 protein levels in the striatum of AAV-shScr– and AAV-shSHMT2–injected mice (n = 3). (C) DARPP-32 (red) and GFP (green) staining in brain sections from AAV-shScr– and AAV-shSHMT2–injected mice. DARPP-32 fluorescence density is quantified within a 220 μm radius around the injection site (n = 4; scale bar: 20 μm). (D) Volcano plot showing markedly altered genes in striatal RNA-seq of SHMT2-knockdown mice compared with controls. DEG cutoff: |log2FC| ≥ 0.25, Padj ≤ 0.05. (E) GO Biological Process enrichment of DEGs from striatal RNA-seq in SHMT2-knockdown versus control mice. Bubble size reflects gene number; color indicates –log10(Padj). (F) IBA1 (magenta) and GFP staining with fluorescence density quantified within a 220 μm radius around the injection site (n = 4; scale bar: 20 μm). (G) GFAP (magenta) and GFP (green) staining with fluorescence density quantified within a 220 μm radius around the injection site (n = 4; scale bar: 20 μm). (H) Cleaved caspase-3 (red) and GFP (green) in striatal sections; percentage of cleaved caspase-3+ cells among GFP+ cells quantified (n = 3; scale bar: 20 μm). (I–M) Behavioral analyses following AAV-shScr or AAV-shSHMT2 injection in 2-month-old mice (n = 12–13). (I) Rotarod performance measured monthly. (J) Beam-crossing time at 2 months after injection. (K–M) Open-field test at 3 months: total distance (K), center distance (L), and center entries (M). Data are shown as the mean ± SEM. Unpaired t test was used for B, C, and F–M. *P < 0.05, **P < 0.01, ***P < 0.001, ****P < 0.0001.