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.

Public Health Relevance

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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS045195-12
Application #
8637112
Study Section
Neuroendocrinology, Neuroimmunology, and Behavior Study Section (NNB)
Program Officer
Gubitz, Amelie
Project Start
2002-12-15
Project End
2015-04-30
Budget Start
2014-05-01
Budget End
2015-04-30
Support Year
12
Fiscal Year
2014
Total Cost
Indirect Cost
Name
Michigan State University
Department
Neurosciences
Type
Schools of Arts and Sciences
DUNS #
City
East Lansing
State
MI
Country
United States
Zip Code
48824
Chen, Chieh V; Brummet, Jennifer L; Jordan, Cynthia L et al. (2016) Down, But Not Out: Partial Elimination of Androgen Receptors in the Male Mouse Brain Does Not Affect Androgenic Regulation of Anxiety or HPA Activity. Endocrinology 157:764-73
Yamada, Shinichiro; Hashizume, Atsushi; Hijikata, Yasuhiro et al. (2016) Decreased Peak Expiratory Flow Associated with Muscle Fiber-Type Switching in Spinal and Bulbar Muscular Atrophy. PLoS One 11:e0168846
Halievski, Katherine; Kemp, Michael Q; Breedlove, S Marc et al. (2016) Non-Cell-Autonomous Regulation of Retrograde Motoneuronal Axonal Transport in an SBMA Mouse Model. eNeuro 3:
Poort, Jessica E; Rheuben, Mary B; Breedlove, S Marc et al. (2016) Neuromuscular junctions are pathological but not denervated in two mouse models of spinal bulbar muscular atrophy. Hum Mol Genet 25:3768-3783
Pfau, Daniel R; Hobbs, Nicholas J; Breedlove, S Marc et al. (2016) Sex and laterality differences in medial amygdala neurons and astrocytes of adult mice. J Comp Neurol 524:2492-502
Xu, Youfen; Halievski, Katherine; Henley, Casey et al. (2016) Defects in Neuromuscular Transmission May Underlie Motor Dysfunction in Spinal and Bulbar Muscular Atrophy. J Neurosci 36:5094-106
Oki, Kentaro; Halievski, Katherine; Vicente, Laura et al. (2015) Contractile dysfunction in muscle may underlie androgen-dependent motor dysfunction in spinal bulbar muscular atrophy. J Appl Physiol (1985) 118:941-52
Halievski, Katherine; Henley, Casey L; Domino, Laurel et al. (2015) Androgen-dependent loss of muscle BDNF mRNA in two mouse models of SBMA. Exp Neurol 269:224-32
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
Chen, Chieh V; Brummet, Jennifer L; Lonstein, Joseph S et al. (2014) New knockout model confirms a role for androgen receptors in regulating anxiety-like behaviors and HPA response in mice. Horm Behav 65:211-8

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