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Fatima Pedrosa Domellof, Jing-Xia Liu, Linda K McLoon; Wnt Expression Patterns in the EOM and Limb Muscles from Patients with Amyotrophic Lateral Sclerosis. Invest. Ophthalmol. Vis. Sci. 2014;55(13):4549.
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Amyotrophic lateral sclerosis (ALS) is a lethal disease characterized by motor neuron degeneration. In contrast to limb skeletal muscle, extraocular muscles (EOM) are largely spared in ALS. Retraction of the innervating motor nerves from the neuromuscular junctions play a part in the pathophysiological process. One signaling factor family implicated in neuromuscular junction formation and plasticity is the Wnt pathway. This study examined the location of 4 members of the Wnt family in the nerve and neuromuscular junctions in EOM and limb muscles from control and ALS subjects.
All muscle specimens were obtained with ethical approval at Umea University. They were kept at -80 until sectioned. Sectioned muscles were immunostained for Wnt1, Wnt3a, Wnt5a, or Wnt 7a and co-stained for neurofilament protein. Co-expression was quantified for each of the 4 Wnts. Additionally, myofiber immunostaining for these 4 Wnts was also determined.
In control muscles, Wnt1 was found in approximately 50% of the axons in EOM and about half that level in limb muscles. This differential was reduced further in the ALS muscles, where it was essentially absent in the nerves from ALS limb muscles. Wnt3a was found in the axons of the majority of nerve fibers in both control and ALS EOM. In contrast, the nerves in the control and ALS limb muscles were relatively devoid of Wnt3a expression. Wnt5a was found in almost all axons from all the muscle specimens examined. Wnt 7a was found in over half of the axons of control and ALS EOM. While only 25% of the control limb muscle axons contained Wnt7a, the number of co-expressing axons was double that level in the ALS limb muscle nerves.
Wnt signaling modulates the formation and function of synapses. As recent studies have proposed that the loss of contact at the neuromuscular junction is an important part of the pathophysiology of ALS, we hypothesize that the up-regulation of specific Wnt molecules in the EOM allows maintenance of functional connections in the ALS patient. Wnt 1, 3a, and 5a have been particularly implicated in modulating neuromuscular junction assembly at the muscle membrane. Also, Wnt levels are modulated by neuronal activity. We hypothesize that these differential Wnt expression patterns could play important roles in maintaining EOM function in the ALS patients.
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