RT Journal Article
SR Electronic
T1 Single-nucleus sequencing reveals enriched expression of genetic risk factors sensitises Motor Neurons to degeneration in ALS
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 2021.07.12.452054
DO 10.1101/2021.07.12.452054
A1 Francesco Limone
A1 Daniel Mordes
A1 Alexander Couto
A1 Olli Pietiläinen
A1 Brian J. Joseph
A1 Aaron Burberry
A1 Sulagna Dia Ghosh
A1 Daniel Meyer
A1 Melissa Goldman
A1 Laura Bortolin
A1 Inma Cobos
A1 Martine Therrien
A1 Beth Stevens
A1 Irena Kadiu
A1 Steven A. McCarroll
A1 Kevin Eggan
YR 2021
UL http://biorxiv.org/content/early/2021/07/13/2021.07.12.452054.abstract
AB Amyotrophic Lateral Sclerosis (ALS) is a fatal neurodegenerative disorder characterised by a progressive loss of motor function. While it is known that the eponymous spinal sclerosis observed upon autopsy is the result of Cortico-Spinal Motor Neuron (CSMN) degeneration, it remains unclear why this neuronal subtype is selectively affected. To understand the unique molecular properties that sensitise deep-layer CSMNs to ALS, we performed RNA sequencing of 79,169 single nuclei from the frontal cortex of patients and controls. In unaffected individuals, we found that expression of ALS risk genes was most significantly enriched only in THY1+ presumptive CSMNs and not in other cortical cell types. In patients, these genetic risk factors, as well as additional genes involved in protein homeostasis and stress responses, were significantly induced in THY1+ CSMNs and a wider collection of deep layer neurons, but not in neurons with more superficial identities. Examination of oligodendroglial and microglial nuclei also revealed patient-specific gene expression changes We show microglial alterations can in part be explained by interactions with degenerating neurons. Overall, our findings suggest the selective vulnerability of CSMNs is due to a “first over the line” mechanism by which their intrinsic molecular properties sensitise them to genetic and mechanistic contributors to degeneration.Competing Interest StatementThe authors have declared no competing interest.