Acetylcholine receptors from human muscle as pharmacological targets for ALS therapy

Eleonora Palma, Jorge Mauricio Reyes-Ruiz, Diego Lopergolo, Cristina Roseti, Cristina Bertollini, Gabriele Ruffolo, Pierangelo Cifelli, E. Onesti, Cristina Limatola, Ricardo Miledi, Maurizio Inghilleri

Research output: Contribution to journalArticlepeer-review

Abstract

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease affecting motor neurons that leads to progressive paralysis of skeletal muscle. Studies of ALS have revealed defects in expression of acetylcholine receptors (AChRs) in skeletal muscle that occur even in the absence of motor neuron anomalies. The endocannabinoid palmitoylethanolamide (PEA) modified the clinical conditions in one ALS patient, improving muscle force and respiratory efficacy. By microtransplanting muscle membranes from selected ALS patients into Xenopus oocytes, we show that PEA reduces the desensitization of acetylcholine-evoked currents after repetitive neurotransmitter application (i.e., rundown). The same effect was observed using muscle samples from denervated (non-ALS) control patients. The expression of human recombinant α1β1γδ (γ-AChRs) and α1β1εδ AChRs (ε-AChRs) in Xenopus oocytes revealed that PEA selectively affected the rundown of ACh currents in ε-AChRs. A clear up-regulation of the α1 subunit in muscle from ALS patients compared with that from non-ALS patients was found by quantitative PCR, but no differential expression was found for other subunits. Clinically, ALS patients treated with PEA showed a lower decrease in their forced vital capacity (FVC) over time as compared with untreated ALS patients, suggesting that PEA can enhance pulmonary function in ALS. In the present work, data were collected from a cohort of 76 ALS patients and 17 denervated patients. Our results strengthen the evidence for the role of skeletal muscle in ALS pathogenesis and pave the way for the development of new drugs to hamper the clinical effects of the disease.

Original languageEnglish
Pages (from-to)3060-3065
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume113
Issue number11
DOIs
Publication statusPublished - Mar 15 2016

Keywords

  • ALS
  • Microtransplantation
  • Muscle AChR
  • QPCR
  • Xenopus oocytes

ASJC Scopus subject areas

  • General

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