Biology subjects

Schweingruber, C.

Publications and source records attributed to Schweingruber, C..

6 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

U7 small nuclear RNA splice-switching therapeutics for STMN2 and UNC13A in Amyotrophic Lateral Sclerosis

TDP-43 nuclear depletion in amyotrophic lateral sclerosis (ALS) causes de-repression of cryptic exons (CEs) in multiple transcripts, including UNC13A and STMN2, disrupting synaptic transmission and neurite outgrowth. We developed a therapeutic U7 snRNA (tU7) approach that suppresses TDP-43-dependent mis-splicing, restores target gene expression, rescues neuronal functions in human iPSC-derived neurons, and shows target engagement in vivo, positioning tU7-mediated splicing correction as a promising therapeutic strategy for ALS.

neuroscience↗

bioRxiv2023

Human motor neurons are rare and can be transcriptomically divided into known subtypes

We performed single-nucleus RNA-sequencing on adult human spinal cord using a neuronal nuclei enrichment strategy. We obtained transcriptomic profiles of >14,000 spinal neurons, including a small population of motor neurons that shares similarities with mouse motor neurons and can be subdivided into alpha and gamma subtypes. We sought to compare our results to those from a recent study by Yadav and colleagues, which provides a single-nucleus transcriptomic atlas of the human spinal cord. While most neuronal nuclei from both studies share similar features, our results from motor neurons differ substantially. We reanalyzed their RNA-sequencing data and provide evidence that the authors incorrectly identified cholinergic cellular debris as motor neuron nuclei in their dataset, raising doubts about their conclusions regarding motor neurons. Our findings underscore the challenges associated with transcriptionally profiling motor neurons from the spinal cord because of their rarity. We propose specific enrichment strategies and recommend important quality control measures for future transcriptional profiling studies involving human spinal cord tissue and rare cell types.

neuroscience↗

bioRxiv2023

Single cell RNA sequencing in isogenic FUS and TARDBP mutant ALS lines reveals early mitochondrial dysfunction as a common pathway in motor neurons

Mutations in the RNA/DNA-binding proteins FUS and TDP-43 cause the fatal disease amyotrophic lateral sclerosis (ALS). The precise mechanisms behind the selective motor neuron degeneration remain unclear and it is uncertain if ALS-causative mutations trigger motor neuron death through shared or distinct pathogenic pathways. To address these two questions, we performed single-cell RNA sequencing across neuron types derived from isogenic induced pluripotent stem cell lines, harbouring FUS P525L, FUS R495X, TARDBP M337V mutations or FUS knockout. The mutations elicited 5- to 15-fold greater transcriptional responses in motor neurons than interneurons. Approximately 20% of transcripts uniquely dysregulated in motor neurons were shared across FUS mutations, with half being driven by FUS gain-of-function. Among these, a majority pointed towards mitochondrial impairments, with attenuated pathways shared with the TARDBP M337V mutation. Meta-analysis demonstrated convergence on mitochondrial dysfunction with C9orf72-ALS patient-derived motor neurons. We observed impaired mitochondrial motility across ALS motor axons, even in isogenic FUS R244C motor neurons, which retain FUS in the nucleus, demonstrating shared toxic gain-of-function mechanisms across FUS- and TARDBP-ALS, uncoupled from protein mislocalization. These early signs of mitochondrial dysfunction unique to motor neurons could have profound implications for their survival and represent promising therapeutic targets across multiple ALS forms.

neuroscience↗

bioRxiv2021

Muscle-secreted neurturin couples myofiber oxidative metabolism and slow motor neuron identity.

Endurance exercise promotes skeletal muscle vascularization, oxidative metabolism, fiber-type switching, and neuromuscular junction integrity. Importantly, the metabolic and contractile properties of the muscle fiber must be coupled to the identity of the innervating motor neuron (MN). Here, we show that muscle-derived neurturin (NRTN) acts on muscle fibers and MNs to couple their characteristics. Using a muscle-specific NRTN transgenic mouse (HSA-NRTN) and RNA-sequencing of MN somas, we observed that retrograde NRTN signaling promotes a shift towards a slow MN identity. In muscle, NRTN increased capillary density, oxidative capacity, and induced a transcriptional reprograming favoring fatty acid metabolism over glycolysis. This combination of effects on muscle and MNs, makes HSA-NRTN mice lean with remarkable exercise performance and motor coordination. Interestingly, HSA-NRTN mice largely recapitulate the phenotype of mice with muscle-specific expression of its upstream regulator PGC-11. This work identifies NRTN as a myokine that couples muscle oxidative capacity to slow MN identity. HIGHLIGHTSO_LINRTN is a myokine induced by physical exercise. C_LIO_LIMuscle-derived NRTN promotes a slow motor neuron identity. C_LIO_LIMuscle-derived NRTN enhances muscle oxidative metabolism. C_LIO_LINRTN improves systemic metabolism, exercise performance and motor coordination. C_LI

physiology↗

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↗