Acetylcholine receptors from human muscle as pharmacological targets for ALS therapy

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. Using microtransplantation of muscle membranes from selected ALS patients into Xenopus oocytes, we show that PEA reduces the desensitization of ACh evoked-currents after repetitive neurotransmitter application (i.e., rundown). The same effect was observed using muscle samples from denervated (non-ALS) control patients. Expressing human recombinant α1β1γδ (γ-AChRs) and α1β1εδ (ε-AChRs) in Xenopus oocytes revealed that PEA selectively affected ACh current rundown in ε-AChRs. A clear up-regulation of α1 subunit in muscle from ALS patients compared to non-ALS patients was found by qPCR, while no differential expression was found for other subunits. Clinically, ALS patients treated with PEA showed a lower decrease over time of their forced vital capacity (FVC %) compared to 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 role of skeletal muscle in ALS pathogenesis and pave the way to develop new drugs to hamper the clinical effects of the disease