The Impact of Androgen Receptor Polyglutamine Expansion on the Motor Unit in SBMA: NMJ Pathology, Motor Unit Vulnerability, and Neurofilament Dysregulation
Abstract
Spinal and bulbar muscular atrophy is an X-linked neurodegenerative disease caused by a CAG-repeat expansion in exon 1 of the androgen receptor gene. Disease pathogenesis requires the presence of androgens, making the disease male specific, although female carriers may show mild muscle cramping. Symptoms include muscle cramps, tremors, and diagnostic findings include fasciculations, sensory dysfunction, dysarthria, and dysphagia. The degeneration and eventual loss of lower motor neurons along with muscle atrophy contribute to the characteristic loss of motor ability. There is currently no cure for this disease. It is known that the loss of lower motor neurons in patients results in a preferential loss of fast-twitch motor units, however the correlation between this preferential vulnerability and NMJ pathology is not understood. We hypothesized that fast twitch motor units would show a higher extent of NMJ pathology in mouse models of SBMA compared to slow twitch motor units of the same model. In addition, based on previous evidence of neurofilament heavy chain (NFH) dysregulation of spinal cord motor neurons in a transgenic SBMA mouse model, we hypothesized that severity of neurofilament dysregulation at the NMJ would also be more severe in fast twitch motor units. Literature on neurofilament dysregulation in SBMA models is modest. We hypothesized that neurofilament subunit dysregulation would not be limited to the reported dysregulation in NFH. We evaluated neurofilament medium chain (NFM), neurofilament light chain (NFL), and NFH expression in multiple models of SBMA to understand if NFH deficits were concomitant with decreased expression of other neurofilament subunits. Because neurofilament subunit expression is altered when there is a deficit in one of the neurofilament subunits, we expected NFL and NFM expression to be altered as well. We hypothesized that the known deficits in translation in SBMA models would contribute to neurofilament subunit deficits.In the present work, we provide evidence for a correlation between NMJ pathology and fast twitch motor unit vulnerability in two mouse models of SBMA. We found glycolytic-to-oxidative fiber type switching and a decrease in myofiber cross sectional area was present, even when NMJ pathology was moderate. When two different fast twitch muscles were evaluated, gastrocnemius showed a higher extent of NMJ pathology than its fast twitch counterpart, tibialis anterior. We hypothesize that this is due to intrinsic ability to focally cluster acetylcholine receptors during development, and therefore, during activation of the developmental program during regeneration. Fast twitch motor unit vulnerability was also correlated with a deficit in neurofilament heavy chain expression at the NMJ. To further our understanding of neurofilaments in SBMA, in vitro (iPSC-derived motor neurons, embryonic spinal cord cultures) and in vivo (transgenic and knock-in mouse spinal cord and sciatic nerve) models were evaluated for neurofilament subunit expression at the protein and mRNA levels. We found that all neurofilament triplet proteins – neurofilament light, medium, and heavy chain – are decreased in these models. These studies revealed a role for neurofilament subunit dysregulation in motor unit degeneration and fast twitch motor unit vulnerability in SBMA pathogenesis. Together these studies highlight the role of both motor neurons and muscle in SBMA pathogenesis and indicate that treatments should focus on eliminating the toxic gain-of-function properties of AR in both of these cell types.
Subject Area
Neurosciences|Biology
Recommended Citation
Molotsky, Elana, "The Impact of Androgen Receptor Polyglutamine Expansion on the Motor Unit in SBMA: NMJ Pathology, Motor Unit Vulnerability, and Neurofilament Dysregulation" (2022). ProQuest ETD Collection - Thomas Jefferson University. AAI30244343.
https://jdc.jefferson.edu/dissertations/AAI30244343
