Acetylcholine receptors from human muscle as pharmacological targets for ALS therapy

Proc Natl Acad Sci U S A. 2016 Mar 15;113(11):3060-5. doi: 10.1073/pnas.1600251113. Epub 2016 Feb 29.

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.

Keywords: ALS; Xenopus oocytes; microtransplantation; muscle AChR; qPCR.

Publication types

  • Comparative Study
  • Randomized Controlled Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Action Potentials / drug effects
  • Adult
  • Aged
  • Aged, 80 and over
  • Amides
  • Amyotrophic Lateral Sclerosis / drug therapy*
  • Amyotrophic Lateral Sclerosis / pathology
  • Amyotrophic Lateral Sclerosis / physiopathology
  • Animals
  • Cell Membrane / drug effects
  • Cell Membrane / transplantation
  • Ethanolamines / pharmacology
  • Ethanolamines / therapeutic use*
  • Female
  • Humans
  • Male
  • Microinjections
  • Middle Aged
  • Molecular Targeted Therapy*
  • Muscle Denervation
  • Muscle, Skeletal / drug effects*
  • Muscle, Skeletal / ultrastructure
  • Neuromuscular Junction / physiopathology
  • Oocytes
  • Palmitic Acids / pharmacology
  • Palmitic Acids / therapeutic use*
  • Receptors, Nicotinic / drug effects*
  • Receptors, Nicotinic / physiology
  • Recombinant Fusion Proteins / drug effects
  • Recombinant Fusion Proteins / genetics
  • Single-Blind Method
  • Xenopus laevis

Substances

  • Amides
  • CHRNE protein, human
  • CHRNG protein, human
  • Ethanolamines
  • Palmitic Acids
  • Receptors, Nicotinic
  • Recombinant Fusion Proteins
  • palmidrol