Slow Congenital Myastenic Syndrome in Transgenic Mouse

Dr. José A. Lasalde-Dominicci (UPR); Christopher, Gómez (University of Minnesota) and Dr. Legier V. Rojas (UCC)

 

The slow-channel syndrome is a model disease of excitatory synaptic degeneration. It is a congenital myasthenic syndrome in which there is progressive degeneration of the neuromuscular junction and muscle atrophy leading to fatigability and weakness due to genetically defective acetylcholine receptors. Since it was first described several other hereditary ion channel disorders affecting nerve or muscle have been identified. In this research effort we are attempting to identify: 1) which spontaneous acetylcholine receptor (AChR) mutations give rise to the slow-channel syndrome (SCS); 2) the nature of the defect in AChR function that causes progressive degeneration of neuromuscular synapses; and 3) the biochemical processes that are activated to cause progressive degeneration of synapses.. We have investigated SCS patients by screening for mutations in the genes encoding the subunits of the acetylcholine receptor of the neuromuscular junction. We have identified the causative mutations in several of these patients. Although all of the mutations appear to cause delayed closure or excessive opening of the acetylcholine receptor ion channel, we have found that the mechanisms responsible for weakness may differ, depending on the molecular and pathological consequences of the mutation. Recently, we have developed several transgenic mouse lines as models of the SCS by expressing mutant acetylcholine receptor subunits in muscle. These transgenic models, expressing human SCS mutations develops the complete spectrum of abnormalities in the disease, including weakness, fatigability, impaired neuromuscular transmission, and calcium ion overload and degeneration of the neuromuscular junctions. As with SCS, the degeneration consists of selective organellar pathology at the neuromuscular junction including degenerating mitochondria and nuclei. In an effort to elucidate the pathological mechanisms that play a role in this selective neuromuscular pathology we have found that there is focal activation of apoptotic pathways at the neuromuscular junctions of the transgenic muscle fibers in some of these mices. To describe how structurally different AChR mutations lead to different phenotypes we propose to use five transgenic lines (WT, L269F, S268F, L262M and C418W) to evaluate the animal motility and behavior during development.. The Behavioral Testing Facilities will be definitely necessary to perform the required behavioral studies.

 

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