Objective: This study mapped baseline stress-response and cell death programs in healthy human striatal populations to identify intrinsic molecular constraints in D2-striosome neurons and their role in HD pathogenesis.

Background: Selective loss of medium spiny neurons (MSNs), particularly D2-striosome neurons, is a hallmark of Huntington’s disease (HD). It remains unclear if this vulnerability arises from disease-induced stress or pre-existing molecular deficiencies.

Method: We integrated pathway and network-coupling analyses on single-nucleus transcriptomic data from normal human striatum (GSE225158, n=6) and an HD dataset (GSE180928). NRF2-mediated antioxidant defense, ferroptosis, mitochondrial quality control (QC), and genome maintenance were quantified using module scores and multivariable regression.

Results: In the normal human striatum, D2-striosome neurons exhibited a pronounced baseline suppression of NRF2-mediated antioxidant signaling, characterized by the coordinated downregulation of canonical target genes such as GPX4, GCLC, and GCLM. While mitochondrial metabolic programs like oxidative phosphorylation and the TCA cycle remained preserved, these neurons showed significantly impaired mitochondrial quality control—marked by the downregulation of OPTN, TBK1, and ATG7—which led to elevated oxidative stress signatures. This upstream oxidative pressure was preferentially routed toward ferroptotic cell death pathways, whereas apoptotic execution remained transcriptionally buffered through the sustained expression of anti-apoptotic regulators. Furthermore, the attenuation of protective genome maintenance factors, such as FAN1, created a chronic, stress-permissive environment that reinforced these vulnerabilities over time. Network-level integration confirmed that these cross-dimensional programs collapse into a tightly integrated vulnerability network centered on the NRF2–ferroptosis axis. Validation using HD datasets further confirmed this impairment of NRF2 signaling, with the suppression of GCLC serving as a key indicator of the degenerative process.

Conclusion: Intrinsic suppression of the NRF2-ferroptosis axis primes D2-striosome neurons for early degeneration. This signaling bottleneck offers a high-priority therapeutic target to restore antioxidant buffering and mitigate selective neuronal loss in HD.

References: 1. Mätlik K, Baffuto M, Kus L, Deshmukh AL, Davis DA, Paul MR et al. Cell-type-specific CAG repeat expansions and toxicity of mutant huntingtin in human striatum and cerebellum. Nat Genet 2024; 56: 383–394.
2. Matsushima A, Pineda SS, Crittenden JR, Lee H, Galani K, Mantero J et al. Transcriptional vulnerabilities of striatal neurons in human and rodent models of huntington’s disease. Nat Commun 2023; 14: 282.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/intrinsic-suppression-of-the-nrf2-ferroptosis-defense-axis-defines-selective-vulnerability-of-d2-striosome-neurons-in-huntingtons-disease/