Kennedy's disease (KD, or spinal and bulbar muscular atrophy) affects men in mid-life and impairs motor function. Men with KD generally leave the work force early and usually require wheelchairs and other specialized aides to perform daily functions. KD is caused by a mutation in the androgen receptor (AR) gene. Mutant AR is presumed to act directly in motoneurons to cause their death, with muscle atrophy as a secondary response. Data from recently developed KD mouse models have taught us that 1) cell dysfunction rather than death underlies early losses in motor function (with motoneuronal cell death representing a late- stage event), and that 2) androgens drive expression of KD (explaining why only men develop KD). The important implication of these findings is that KD is treatable by limiting AR activity. Our novel myogenic mouse model of KD, expressing pathogenic AR only in muscle, shows the same disease phenotype as seen in other mouse models of KD, namely androgen-dependent losses in cell and motor function. Our model however offers the unexpected and novel perspective that AR may act in muscle fibers and not motoneurons to trigger KD, since the AR transgene is expressed only in skeletal muscle fibers and not motoneurons. Preliminary evidence indicates that pathogenic expression of AR in muscle has two distinct consequences: it impairs the function of motoneurons by causing defects in axonal transport and impairs muscle function by altering its contraction kinetics and overall strength. Thus, the broad goal of this project is to identify the mechanisms by which pathogenic AR expressed only in muscle fibers impairs both muscles and motoneurons, and determine how these events together cause behavioral dysfunction. To achieve this goal, we propose to assess muscle contraction kinetics and synaptic strength, parameters that have not been assessed in any KD model, using standard in vitro electrophysiological approaches. Not only will these experiments provide information about the factors causing a loss of muscle function, but they will inform us about whether synaptic dysfunction, muscle dysfunction or both triggers behavioral dysfunction. We also propose to examine the structure of neuromuscular synapses and monitor directly the transport of moving cargo in living mouse nerve, using a novel technique recently worked out for mammals. While neuromuscular synapses have been widely shown to be affected in motoneuron diseases, including amyotrophic lateral sclerosis and spinal muscular atrophy, neuromuscular synapses have yet to be examined in any KD model. Thus, these experiments are likely to yield new, important information about the critical mechanisms underlying the loss of motor function in KD. More importantly, because our model suggests that the critical pathogenic events in KD originate in muscle, our work may identify new targets in muscle for treating KD.
Kennedy's disease (KD) is a disabling neurodegenerative disease that affects men in mid life and has no known treatment or cure. Data from our KD mouse model suggests that the disease begins in muscle. Treatments that target muscle may offer new hope for treating KD.
|Renier, Kayla J; Troxell-Smith, Sandra M; Johansen, Jamie A et al. (2014) Antiandrogen flutamide protects male mice from androgen-dependent toxicity in three models of spinal bulbar muscular atrophy. Endocrinology 155:2624-34|
|Waddell, Jaylyn; Bowers, J Michael; Edwards, N Shalon et al. (2013) Dysregulation of neonatal hippocampal cell genesis in the androgen insensitive Tfm rat. Horm Behav 64:144-52|
|Smith, Milo R; Hamson, Dwayne K; Poort, Jessica E et al. (2012) Ontogeny of androgen receptor expression in spinal nucleus of the bulbocavernosus motoneurons and their target muscles in male mice. Neurosci Lett 513:119-23|
|Johansen, Jamie A; Troxell-Smith, Sandra M; Yu, Zhigang et al. (2011) Prenatal flutamide enhances survival in a myogenic mouse model of spinal bulbar muscular atrophy. Neurodegener Dis 8:25-34|
|Kemp, Michael Q; Poort, Jessica L; Baqri, Rehan M et al. (2011) Impaired motoneuronal retrograde transport in two models of SBMA implicates two sites of androgen action. Hum Mol Genet 20:4475-90|
|Zuloaga, Damian G; Poort, Jessica E; Jordan, Cynthia L et al. (2011) Male rats with the testicular feminization mutation of the androgen receptor display elevated anxiety-related behavior and corticosterone response to mild stress. Horm Behav 60:380-8|
|Sato, Satoru M; Johansen, Jamie A; Jordan, Cynthia L et al. (2010) Membrane androgen receptors may mediate androgen reinforcement. Psychoneuroendocrinology 35:1063-73|
|Pappas, Samuel S; Tiernan, Chelsea T; Behrouz, Bahareh et al. (2010) Neonatal androgen-dependent sex differences in lumbar spinal cord dopamine concentrations and the number of A11 diencephalospinal dopamine neurons. J Comp Neurol 518:2423-36|
|Johnson, Ryan T; Breedlove, S Marc; Jordan, Cynthia L (2010) Astrocytes in the amygdala. Vitam Horm 82:23-45|
|Johansen, Jamie A; Yu, Zhigang; Mo, Kaiguo et al. (2009) Recovery of function in a myogenic mouse model of spinal bulbar muscular atrophy. Neurobiol Dis 34:113-20|
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