Pathologically mislocalised TDP-43 in upper motor neurons causes a die-forward spread of ALS-like pathogenic changes throughout the mouse corticomotor system.

Autor: Reale LA; Menzies Institute for Medical Research, University of Tasmania, 17 Liverpool Street, Hobart, TAS 7000, Australia., Dyer MS; Menzies Institute for Medical Research, University of Tasmania, 17 Liverpool Street, Hobart, TAS 7000, Australia., Perry SE; The Wicking Dementia Centre, University of Tasmania, 17 Liverpool Street, Hobart, TAS 7000, Australia., Young KM; Menzies Institute for Medical Research, University of Tasmania, 17 Liverpool Street, Hobart, TAS 7000, Australia., Dickson TC; Menzies Institute for Medical Research, University of Tasmania, 17 Liverpool Street, Hobart, TAS 7000, Australia., Woodhouse A; The Wicking Dementia Centre, University of Tasmania, 17 Liverpool Street, Hobart, TAS 7000, Australia., Blizzard CA; Menzies Institute for Medical Research, University of Tasmania, 17 Liverpool Street, Hobart, TAS 7000, Australia; Tasmanian School of Medicine, University of Tasmania, 17 Liverpool Street, Hobart, TAS 7000, Australia. Electronic address: Catherine.Blizzard@utas.edu.au.
Jazyk: angličtina
Zdroj: Progress in neurobiology [Prog Neurobiol] 2023 Jul; Vol. 226, pp. 102449. Date of Electronic Publication: 2023 Apr 01.
DOI: 10.1016/j.pneurobio.2023.102449
Abstrakt: Alterations in upper motor neuron excitability are one of the earliest phenomena clinically detected in ALS, and in 97 % of cases, the RNA/DNA binding protein, TDP-43, is mislocalised in upper and lower motor neurons. While these are two major pathological hallmarks in disease, our understanding of where disease pathology begins, and how it spreads through the corticomotor system, is incomplete. This project used a model where mislocalised TDP-43 was expressed in the motor cortex, to determine if localised cortical pathology could result in widespread corticomotor system degeneration. Mislocalised TDP-43 caused layer V excitatory neurons in the motor cortex to become hyperexcitable after 20 days of expression. Following cortical hyperexcitability, a spread of pathogenic changes through the corticomotor system was observed. By 30 days expression, there was a significant decrease in lower motor neuron number in the lumbar spinal cord. However, cell loss occurred selectively, with a significant loss in lumbar regions 1-3, and not lumbar regions 4-6. This regional vulnerability was associated with alterations in pre-synaptic excitatory and inhibitory proteins. Excitatory inputs (VGluT2) were increased in all lumbar regions, while inhibitory inputs (GAD65/67) were increased in lumbar regions 4-6 only. This data indicates that mislocalised TDP-43 in upper motor neurons can cause lower motor neuron degeneration. Furthermore, cortical pathology increased excitatory inputs to the spinal cord, to which local circuitry compensated with an upregulation of inhibition. These findings reveal how TDP-43 mediated pathology may spread through corticofugal tracts in ALS and identify a potential pathway for therapeutic intervention.
Competing Interests: Declaration of Competing Interest The authors declare that no competing interests exist. Data statement Data supporting the findings of this study are available from the corresponding author upon request.
(Copyright © 2023 Elsevier Ltd. All rights reserved.)
Databáze: MEDLINE
Externí odkaz: