Single-nucleus sequencing reveals enriched expression of genetic risk factors in extratelencephalic neurons sensitive to degeneration in ALS.
Francesco LimoneDaniel A MordesAlexander CoutoBrian J JosephJana M MitchellMartine TherrienSulagna Dia GhoshDaniel MeyerYingying ZhangMelissa GoldmanLaura BortolinInma CobosBeth StevensSteven A McCarrollIrena KadiuAaron BurberryOlli PietiläinenKevin EgganPublished in: Nature aging (2024)
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.
Keyphrases
- amyotrophic lateral sclerosis
- end stage renal disease
- newly diagnosed
- ejection fraction
- risk factors
- spinal cord
- poor prognosis
- single cell
- genome wide
- multiple sclerosis
- cell proliferation
- signaling pathway
- patient reported outcomes
- cell death
- patient reported
- neuropathic pain
- long non coding rna
- cell cycle arrest
- drug induced
- stress induced