The role of the protein, αkap, in the structure and maintenance of the mouse neuromuscular junction

Part of my current research focuses on understanding the dynamics of pathological loss and change of neuromuscular synapses that allow for neural control of muscle function in the motor neuron disease, amyotrophic lateral sclerosis (ALS), commonly known as “Lou Gehrig’s Disease”. In this disease, pathological changes occur that sadly cause motor neuron-muscle communication and activity dysfunction, which results in skeletal muscle wasting, paralysis, motor neuron death, and eventually death of the afflicted person. I study the literature to understand mechanisms of how such pathology may occur to help focus studies on targeting therapies to be more effective in treating ALS.


The junction between the terminal synapse of the spinal motor neuron and the peripheral musculature (found in the limbs and elsewhere) is characterized by synapse whereby the neuron releases acetylcholine to activate the nicotinic acetylcholine receptors (AchRs) that are clustered at the post-synaptic membrane of the muscle. These receptors cluster at this synapse for effective communication with the motor neuron, and rearrange in response to disease or injury to the neuron or nerve. Improving stability of this neuron-AchR interaction, or helping achieve its re-connection could result in less disuse atrophy of the muscles and improve neurological function. 

A recent paper in the Journal of Neuroscience by Martinez-Pena y Valenzuela et al. (35[13]: 5118-5127; doi: 10.1523/JNEUROSCI.3951-14.2015) discusses the investigation and results concerning the importance of a particular muscle-specific nonkinase anchoring protein (αkap), encoded within the calcium/calmodulin kinase II (camk2) α gene in living animals, as prior research has already implicated this protein in such a role in cell culture. The authors found that knocking-down the expression of αkap reduced the amount of AchRs at the muscular post-synapse, and prevented new placement and reduced the recycling of these receptors at the synapse. Importantly, blocking αkap led to breakdown of the entire neuromuscular synapse, implicating a very large role for this protein in maintaining normal structure and function of the neuromuscular synapse. This paper is important as it implicates dysfunction in αkap synthesis or incorporation at the neuromuscular synapse as a potential mechanism to target in treating disease progression in ALS and other related disorders. 

Martinez-Pena Y Valenzuela I, Aittaleb M, Chen PJ, Akaaboune M. (2015) The Knockdown of αkap Alters the Postsynaptic Apparatus of Neuromuscular Junctions in Living Mice. J Neurosci. 2015 Apr 1;35(13):5118-27. doi: 10.1523/JNEUROSCI.3951-14.2015.

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