The Landmark Discovery: Cedars-Sinai Leads Breakthrough in MS Research

Researchers at Cedars-Sinai Medical Center, in collaboration with the University of California, San Francisco (UCSF) and the University of Cambridge, have pinpointed a critical vulnerability in the brain that explains why multiple sclerosis (MS) progressively damages cognitive functions. Published in the prestigious journal Nature on April 1, 2026, two companion studies reveal that specific neurons expressing the CUX2 protein—known as CUX2-positive upper-layer cortical excitatory neurons (L2/3ENs)—are exceptionally susceptible to DNA damage during neuroinflammation. This finding shifts the spotlight from the traditional focus on myelin loss to direct neuronal death in the brain's gray matter, offering fresh hope for protecting thinking and memory centers in MS patients.

David H. Rowitch, MD, PhD, deputy director for Research at Cedars-Sinai Guerin Children’s and professor of Paediatrics at the University of Cambridge, described these CUX2 neurons as a “canary in the coal mine” for MS-affected brains. Their early demise signals broader trouble, and safeguarding them could halt disease progression. Stephen Fancy, PhD, DVM, from UCSF's Weill Institute for Neurosciences, highlighted the cells' built-in repair mechanisms, noting excitement over potential therapeutic targets.

This discovery emerges from Cedars-Sinai's robust neuroscience research ecosystem, bolstered by its Health Sciences University, which integrates cutting-edge education with clinical breakthroughs. The work underscores how academic medical centers like Cedars-Sinai drive higher education in neurology, training the next generation of researchers tackling neurodegenerative diseases.

Multiple Sclerosis Explained: From Myelin to Gray Matter Atrophy

Multiple sclerosis is a chronic autoimmune disorder where the immune system mistakenly attacks the central nervous system, primarily targeting myelin—the protective sheath around nerve fibers. This demyelination disrupts signal transmission, causing symptoms like fatigue, mobility issues, numbness, and vision problems. In the United States, nearly 1 million people live with MS, according to the National Multiple Sclerosis Society, with women three times more likely to be diagnosed than men. Prevalence peaks between ages 20 and 50, and while exact 2026 figures are emerging, estimates hover around 1 million cases nationwide, with higher rates in northern states away from the equator.

Traditionally, MS research emphasized white matter lesions visible on MRI scans. However, progressive MS—especially secondary progressive MS (SPMS), affecting about 65% of patients over time—features insidious gray matter thinning in the cortex, leading to cognitive impairment in up to 70% of cases. Memory loss, executive dysfunction, and processing speed deficits erode quality of life, yet their causes remained elusive until now. This Cedars-Sinai-led research bridges that gap, linking inflammation to irreversible neuron loss.

CUX2 Neurons: High-Performers with a Hidden Achilles' Heel

CUX2 neurons reside in layers 2 and 3 of the cerebral cortex, the brain's outer gray matter responsible for higher-order functions like decision-making, planning, and sensory integration. These excitatory neurons, marked by the CUT-like homeobox 2 (CUX2) transcription factor, emerge during early brain development under intense replicative stress—rapid division and wiring demand high metabolic activity, generating reactive oxygen species (ROS) that nick DNA strands.

To cope, CUX2 neurons evolved robust DNA damage response (DDR) pathways, relying on activating transcription factor 4 (ATF4) to activate repair genes like CIRBP, UBA52, and EBF1. This system handles double-strand breaks via non-homologous end joining (NHEJ), ensuring survival. But in MS, chronic inflammation—fueled by cytokines like interferon-gamma (IFNγ)—spikes ROS, overwhelming repair. Unlike oligodendrocytes (myelin producers) or deeper-layer neurons, CUX2 cells burn out fastest, explaining selective loss in cortical lesions.

As Nancy L. Sicotte, MD, chair of Neurology at Cedars-Sinai, emphasized, these insights mark a milestone in decoding neurological pathways.

Unraveling the Mystery: Study Methods and Rigorous Evidence

The dual studies employed single-nucleus RNA sequencing (snRNA-seq) on postmortem MS brain tissue from the UK Multiple Sclerosis Tissue Bank (12 MS cases vs. 9 controls), revealing upregulated DDR/apoptosis genes and DNA damage markers (γH2AX, 53BP1 foci) specifically in CUX2+ L2/3ENs. Mouse models mimicked MS: diphtheria toxin ablation (DTA) for demyelination, Myrf conditional knockout for oligodendrocyte loss, and astrocyte-specific IFNγ overexpression (AS-IFNγ) for inflammation without demyelination.

Longitudinal tracking showed L2/3 thinning and 18-27% CUX2 neuron depletion by 17-27 weeks, with oxidative damage (8-OHdG). Genetic knockouts confirmed Cux2 and Atf4 necessity: double knockouts exacerbated loss under cuprizone-induced demyelination or neonatal hypoxia/LPS. In vitro, IFNγ triggered ROS and comet-tail DNA damage in human iPSC-derived neurons, rescued by antioxidants or CUX2 overexpression. Read the primary study here.

DNA Damage: The Overlooked Culprit in MS Progression

DNA double-strand breaks accumulate 2.5-fold faster in MS lesion neurons, per sequencing data. IFNγ from T-cells sparks nitrosative/oxidative stress, fraying DNA. While white matter focuses on remyelination, gray matter neurons face intrinsic peril: high transcription rates amplify errors. In progressive MS, where DMTs (disease-modifying therapies) like ocrelizumab curb relapses but not atrophy, this explains persistent decline.

Cedars-Sinai's analysis of pan-nuclear 53BP1 and pseudotime trajectories pinpointed L2/3ENs' trajectory toward apoptosis, validating vulnerability across models.

ATF4: Guardian of Neuronal DNA Repair

The second Nature paper dissects ATF4's role: it phosphorylates ATM (ataxia telangiectasia mutated) via CIRBP, kickstarting NHEJ. ATF4 knockout (Emx1-Cre; Atf4^fl/fl) slashed CUX2 numbers by 30-50% at postnatal day 7, with p53-dependent progenitor death. CIRBP knockdown mimicked this, impairing ATM activation. Access the companion paper.

This developmental adaptation repurposed for inflammation protection fails in MS, suggesting ATF4 agonists as novel therapies.

Cognitive Toll: Why MS Hits Thinking Hard

Up to 65% of MS patients face cognitive issues, correlating with cortical thinning. CUX2 loss disrupts executive networks, mirroring autism/epilepsy overlaps. Real-world cases: patients report “brain fog” despite stable white matter scans. Cedars-Sinai's multimodal approach—genomics, imaging, models—illuminates this, guiding precision neurology education.

Collaborative Power: Universities Fueling MS Innovation

UCSF's glial biology expertise, Cambridge's stem cell prowess, and Cedars-Sinai's clinical cohorts exemplify higher ed synergy. Daniel Geschwind (UCLA) and Ben Emery (UCSF) contributed genomics; Brian Popko (Northwestern) pathology. Such partnerships train PhD students in bioinformatics, neuroimmunology—vital for US research pipeline.

Cedars-Sinai Health Sciences University: Hub for MS Research Training

Cedars-Sinai's new Health Sciences University merges 16 residencies, 76 fellowships with labs like Neuroimmunology. Faculty like Sicotte mentor on MS biomarkers, preparing clinician-scientists. Amid 2026 hiring surges in research faculty, it positions LA as neurology epicenter. Learn more on their advances.

MS in America: 2026 Stats and Treatment Landscape

Nearly 1 million Americans battle MS; annual costs exceed $85 billion. FDA-approved DMTs (20+) like Kesimpta reduce relapses 50-70%, but progressive forms lag. 2026 saw glatiramer generics approved; tolebrutinib awaits amid liver concerns. Lifestyle—exercise, vitamin D—complements, per National MS Society.

Toward New Therapies: DNA Protection Horizons

Target ROS (NAC, lipoic acid), IFNγ pathways, or ATF4 boosters. Genetic variants (rs10191329) predict risk, enabling personalized care. Clinical trials could test NHEJ enhancers, revolutionizing progressive MS.

Careers in MS Research: Opportunities at the Forefront

This discovery spotlights demand for neuroscientists, geneticists. Cedars-Sinai, UCSF seek faculty; US universities expand MS programs amid NIH funding. Aspiring researchers: pursue PhDs in neuroimmunology for impactful roles.

Photo by Robina Weermeijer on Unsplash