At the Origin of ALS a Miscommunication Between Muscle and Nerve
The study, coordinated by Antonio Musarò of Sapienza University of Rome has been published on Antioxidant and redox signaling (Ars) and supported by Fondazione Roma, IIT-Sapienza, Pasteur Institute-Italia, and Telethon.The researchers disclosed the molecular mechanisms involved in the dismantlement of neuromuscular junctions (NMJ), triggered by oxidative stress.
NMJ degeneration represents a hallmark of aging sarcopenia as well as of several neuromuscular diseases, including Amyotrophic Lateral Sclerosis (ALS), a progressive neurodegenerative disease due to mutation in SOD1 gene.NMJ serve as the interface between the nervous and skeletal muscular systems, and thus they may receive pathophysiological input of both pre- and post-synaptic origin. However, controversy exists over whether NMJ dismantlement is a pathogenic event directly associated with the primary defects occurring in motor neurons or whether it occurs independently from motor neuron degeneration.
To address this question, the Musarò's team made use of transgenic mice in which the mutated gene involved in familial ALS has been selectively expressed in skeletal muscle.
"We have demonstrated - Musarò said- that an alteration in skeletal muscle induces a dismantlement of the neuromuscular junction. We then identified the molecular mechanism at the base of the NMJ dismantlement and found that this depends on the activation of a protein kinase, known as PKC theta".
To causally link the activation of PKC theta expression with the dismantlement of NMJ, the authors of the study interfered with its activity, treating the mice with a pharmacological inhibitor of PKC theta.
"We demonstrated, Musarò said, that the inhibition of PKC theta activity was sufficient to rescue the morphological complexity of NMJ and to stabilize the acetylcholine receptor turnover".
"Our study, Musarò said, supports the concept of a "dying-back" process in which the earliest presymptomatic functional and pathological changes observed in ALS and neuromuscular diseases are occurring distally at the NMJ, and suggests the possibility of developing a pharmacological intervention to attenuate muscle-nerve dysfunction, NMJ loss and eventually disease progression in a sort of "saving-back" process".
Antonio Musarò, Department of Anatomical, Histological, Locomotor and Legal Medicine Sciences, Sapienza University of Rome