Increase of HCN current in SOD1-associated amyotrophic lateral sclerosis.

Autor:	Lai HJ; Department of Neurology, National Taiwan University Hospital and National Taiwan University College of Medicine, Taipei, 100, Taiwan., Kuo YC; Department of Neurology, National Taiwan University Hospital and National Taiwan University College of Medicine, Taipei, 100, Taiwan.; Department of Neurology, National Taiwan University Hospital, Hsinchu Branch, Hsinchu City, 300, Taiwan., Ting CH; Garage Brain Science, B201, Central Taiwan Innovation Campus, Ministry of Economic Affairs, Nantou City, 540219, Taiwan., Yang CC; Department of Neurology, National Taiwan University Hospital and National Taiwan University College of Medicine, Taipei, 100, Taiwan., Kao CH; Department of Neurology, National Taiwan University Hospital and National Taiwan University College of Medicine, Taipei, 100, Taiwan., Tsai YC; Department of Neurology, National Taiwan University Hospital and National Taiwan University College of Medicine, Taipei, 100, Taiwan., Chao CC; Department of Neurology, National Taiwan University Hospital and National Taiwan University College of Medicine, Taipei, 100, Taiwan., Hsueh HW; Department of Neurology, National Taiwan University Hospital and National Taiwan University College of Medicine, Taipei, 100, Taiwan., Hsieh PF; Department of Neurology, National Taiwan University Hospital and National Taiwan University College of Medicine, Taipei, 100, Taiwan., Chang HY; Garage Brain Science, B201, Central Taiwan Innovation Campus, Ministry of Economic Affairs, Nantou City, 540219, Taiwan.; YEEFAN MED INC, Temple City, CA 91780, USA., Wang IF; Garage Brain Science, B201, Central Taiwan Innovation Campus, Ministry of Economic Affairs, Nantou City, 540219, Taiwan.; YEEFAN MED INC, Temple City, CA 91780, USA., Tsai LK; Department of Neurology, National Taiwan University Hospital and National Taiwan University College of Medicine, Taipei, 100, Taiwan.; Department of Neurology, National Taiwan University Hospital, Hsinchu Branch, Hsinchu City, 300, Taiwan.
Jazyk:	angličtina
Zdroj:	Brain : a journal of neurology [Brain] 2024 Aug 01. Date of Electronic Publication: 2024 Aug 01.
DOI:	10.1093/brain/awae248
Abstrakt:	The clinical manifestations of sporadic amyotrophic lateral sclerosis (ALS) vary widely. However, the current classification of ALS is mainly based on clinical presentations, while the roles of electrophysiological and biomedical biomarkers remain limited. Herein, we investigated a group of patients with sporadic ALS and an ALS mouse model with superoxide dismutase 1 (SOD1)/G93A transgenes using nerve excitability tests (NET) to investigate axonal membrane properties and chemical precipitation, followed by enzyme-linked immunosorbent assay analysis to measure plasma misfolded protein levels. Six of 19 patients (31.6%) with sporadic ALS had elevated plasma misfolded SOD1 protein levels. In sporadic ALS patients, only those with elevated misfolded SOD1 protein levels showed an increased inward rectification in the current-threshold (I/V) curve and an increased threshold reduction in the hyperpolarizing threshold electrotonus (TE) in the NET study. Two familial ALS patients with SOD1 mutations also exhibited similar electrophysiological patterns of NET. For patients with sporadic ALS showing significantly increased inward rectification in the I/V curve, we noted an elevation in plasma misfolded SOD1 level, but not in total SOD1, misfolded C9orf72, or misfolded phosphorylated TDP43 levels. Computer simulations demonstrated that the aforementioned axonal excitability changes are likely associated with an increase in hyperpolarization-activated cyclic nucleotide-gated (HCN) current. In SOD1/G93A mice, NET also showed an increased inward rectification in the I/V curve, which could be reversed by a single injection of the HCN channel blocker, ZD7288. Daily treatment of SOD1/G93A mice with ZD7288 partially prevented the early motor function decline and spinal motor neuron death. In summary, sporadic ALS patients with elevated plasma misfolded SOD1 exhibited similar patterns of motor axonal excitability changes as familial ALS patients and ALS mice with mutant SOD1 genes, suggesting the existence of SOD1-associated sporadic ALS. The observed NET pattern of increased inward rectification in the I/V curve was attributable to an elevation in the HCN current in SOD1-associated ALS. (© The Author(s) 2024. Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)
Databáze:	MEDLINE
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