Amyotrophic Lateral Sclerosis Research
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Using single-nucleus RNA sequencing data from patients with sporadic amyotrophic lateral sclerosis cortices, the authors find that higher expression of ALS risk genes is accompanied by upregulation of stress responses in groups of extratelencephalic neurons.
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Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder characterized by a progressive loss of motor function linked to degenerating extratelencephalic neurons/Betz cells (ETNs). The reasons why these neurons are selectively affected remain unclear. Here, to understand the unique molecular properties that may sensitize ETNs to ALS, we performed RNA sequencing of 79,169 single nuclei from cortices of patients and controls. In both patients and unaffected individuals, we found significantly higher expression of ALS risk genes in THY1+ ETNs, regardless of diagnosis. In patients, this was accompanied by the induction of genes involved in protein homeostasis and stress responses that were significantly induced in a wide collection of ETNs. Examination of oligodendroglial and microglial nuclei revealed patient-specific downregulation of myelinating genes in oligodendrocytes and upregulation of an endolysosomal reactive state in microglia. Our findings suggest that selective vulnerability of extratelencephalic neurons is partly connected to their intrinsic molecular properties sensitizing them to genetics and mechanisms of degeneration.
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@article{Limone2024Single,
title = {Single-nucleus sequencing reveals enriched expression of genetic risk factors in extratelencephalic neurons sensitive to degeneration in ALS},
author = {Francesco Limone and Daniel A. Mordes and Alexander Benavides Couto and Brian Joseph and Jana M. Mitchell and Martine Therrien and Sulagna Ghosh and Daniel Meyer and Yingying Zhang and Melissa Goldman and Laura Bortolin and Inma Cobos and Beth Stevens and Steven A. McCarroll and Irena Kadiu and Aaron Burberry and Olli Pietiläinen and Kevin Eggan},
journal = {Nature Aging},
year = {2024},
doi = {10.1038/s43587-024-00640-0},
url = {https://doi.org/10.1038/s43587-024-00640-0}
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