Biology subjects

Nichterwitz, S.

Publications and source records attributed to Nichterwitz, S..

4 recordsLinked to original sources

bioRxiv2025

Reevaluating the Role of Beta2-Microglobulin: New Insights on Selective Vulnerability in ALS Pathology

Amyotrophic lateral sclerosis (ALS) is characterized by the selective loss of motor neurons (MNs). Why these neurons show particular vulnerability in ALS is still debated, and also why certain MNs remain resilient. We investigated the importance of the human leukocyte antigen (HLA) and particularly beta2-microglobulin ({beta}2m) in MN susceptibility to ALS as these molecules have been implicated both in prolonging and shortening disease. RNA-sequencing demonstrated that disease-resistant oculomotor neurons (OMNs) and Onufs MNs had similar {beta}2m and HLA mRNA levels to vulnerable spinal MNs in control tissues. Thus, baseline differences in these transcripts do not explain the differential vulnerabilities of these neurons to disease. Nonetheless, the HLA protein level showed an inverse correlation with spinal MN size, where large MNs, which are lost early in ALS, had low HLA levels. HLA protein levels were also reduced in end-stage ALS patient spinal MNs, while remaining unchanged in OMNs with disease. Spinal MNs uniquely exhibited a significant upregulation of {beta}2m and HLA-C transcripts with disease, likely as a protective compensatory response. Thus, {beta}2m and HLA may relate to vulnerability to ALS. Cross-breeding of {beta}2m knockout mice with SOD1G93A ALS mice resulted in modest transient worsening of functional motor performance, but did not affect life span. There was partial preservation of innervation of particular muscles in SOD1G93A mice lacking {beta}2m, which was insufficient to improve motor behavior. These findings indicate that {beta}2m and HLAs are dynamically regulated in ALS, and may influence MN vulnerability, but they are not major disease modifiers in ALS.

neuroscience↗

bioRxiv2025

A single cell multi-omic analysis identifies molecular and gene-regulatory mechanisms dysregulated in the developing Down syndrome neocortex

Down syndrome is the most common genetic cause of intellectual disability, presenting with cognitive, learning, memory, and language deficits. The cellular and molecular mechanisms driving this disorder remain unclear, limited by a lack of systematic studies in the developing human brain. Here, we leveraged single-nucleus multi-omics to profile the mid-gestation neocortex in a cohort of 26 donors. We observed a reduction in neural progenitors and corticothalamic neurons and concomitant increase of intratelencephalic neurons, accompanied by accelerated time to neuronal specification. We uncovered widespread changes in gene expression, chromatin accessibility and cell interaction networks impacting neurogenesis, specification and maturation and gene-regulatory networks directing these processes, including those downstream of transcription factors encoded in chromosome 21. Finally, we identified cell-specific molecular pathways shared with other neurodevelopmental disorders as well as heritability enrichment of GWAS signals in altered chromatin. Together, our data revealed a cascade of molecular dysregulation outlining the earliest steps in Down syndrome, providing a foundation for future therapeutic targets.

genomics↗

bioRxiv2024

Transcriptional modulation unique to vulnerable motor neurons predict ALS across species and SOD gene mutations

Amyotrophic lateral sclerosis (ALS) is characterized by the progressive loss of motor neurons that innervate skeletal muscles. However, certain motor neuron groups including ocular motor neurons, are relatively resilient. To reveal key drivers of resilience versus vulnerability in ALS, we investigate the transcriptional dynamics of four distinct motor neuron populations in SOD1G93A ALS mice using LCM-seq and single molecule fluorescent in situ hybridization. We find that resilient ocular motor neurons regulate few genes in response to disease. Instead, they exhibit high baseline gene expression of neuroprotective factors including En1, Pvalb, Cd63 and Gal, some of which vulnerable motor neurons upregulate during disease. Vulnerable motor neuron groups upregulate both detrimental and regenerative responses to ALS and share pathway activation, indicating that breakdown occurs through similar mechanisms across vulnerable neurons, albeit with distinct timing. Meta-analysis across four rodent mutant SOD1 motor neuron transcriptome datasets identify a shared vulnerability code of 39 genes including e.g Atf4, Nupr1, Ddit3 and Penk, involved in apoptosis, as well as a proregenerative and anti-apoptotic signature consisting of Atf3, Vgf, Ina, Sprr1a, Fgf21, Gap43, Adcyap1, and Mt1. Machine learning using genes upregulated in SOD1G93A spinal motor neuron predicts disease in human stem cell-derived SOD1E100G motor neurons, and shows that dysregulation of VGF, INA, PENK and NTS are strong disease-predictors across species and SOD1 mutations. Our study reveals motor neuron population-specific gene expression and temporal disease-induced regulation that together provide a basis to explain ALS selective vulnerability and resilience and that can be used to predict disease.

neuroscience↗

bioRxiv2018

LCM-seq reveals unique transcriptional adaption mechanisms of resistant neurons in spinal muscular atrophy

Somatic motor neurons are selectively vulnerable in spinal muscular atrophy (SMA), a lethal disease caused by a deficiency of the ubiquitously expressed survival of motor neuron (SMN) protein. However, some brainstem motor neuron groups, including oculomotor and trochlear (ocular), which innervate the muscles around the eyes, are for unknown reasons spared. Here, using laser capture microdissection coupled with RNA sequencing (LCM-seq), we investigate the transcriptional dynamics in discrete neuronal populations in health and SMA to reveal mechanisms of vulnerability and resistance. Using gene correlation network analysis, we reveal a p53-mediated stress response that is intrinsic to all somatic motor neurons independent of their vulnerability, but absent in resistant red nucleus and visceral motor neurons. However, our temporal and spatial differential expression analysis across neuron types clearly demonstrates that the majority of SMA-induced modulations are cell-type specific. Notably, using gene ontology and protein-network analyses we show that ocular motor neurons present unique disease-adaptation mechanisms that could explain their resilience. In particular, ocular motor neurons up-regulate; i) Syt1, Syt5 and Cplx2, which modulate neurotransmitter release; ii) the motor neuron survival factors Chl1 and Lif, iii) Aldh4, that can protect cells from oxidative stress and iv) the caspase inhibitor Pak4. In conclusion, our in-depth longitudinal analysis of gene expression changes in SMA reveal novel cell-type specific changes that present compelling targets for future gene therapy studies aimed towards preserving vulnerable motor neurons.

neuroscience↗