Selective neuronal degeneration is a distinguishing feature of many adult onset neurodegenerative disorders. Among these chronic diseases of the nervous system are ones caused by expansions of CAG/glutamine tracts. Kennedy disease, a member of this group, is characterized by degeneration of lower motor neurons due to an expanded CAG repeat in the first exon of the androgen receptor gene. Data from several laboratories including our own demonstrate that the mutant androgen receptor protein misfolds, aggregates and abnormally interacts with other proteins, leading to homone dependent lower motor neuron degeneration and skeletal muscle atrophy. Despite significant advances in unraveling the disease basis, pathways by which the mutant androgen receptor mediates selective motor neuron pathology remain inadequately understood. Recent work has highlighted the importance of abnormal cell interactions and the involvement of non-neuronal cells in the pathogenesis of certain polyglutamine and motor neuron diseases. The objective of this proposal is to identifiy the pathways by which the expanded glutamine androgen receptor causes selective neuronal loss. Our central hypothesis is that the mutant androgen receptor protein exerts toxic effects on both lower motor neurons and the skeletal muscle cells they innervate that together lead to selective neuronal pathology. This hypothesis is based on characterization of our recently developed knock-in mouse model of Kennedy disease. We find that this model reproduces the neuromuscular and systemic manifestations of this disorder. Furthermore, muscle pathology, which is accompanied by evidence of a primary myopathy and by activation of the unfolded protein response, precedes motor neuron loss, suggesting a role for non-cell autonomous toxicity. Biochemical, cellular and genetic approaches will be employed to gain a better understanding of the mechanisms leading to skeletal muscle pathology (Aim 1), the role of non-cell autonomous toxicity (Aim 2), and the contribution of the unfolded protein response to the development of the disease phenotype (Aim 3). The relevance of the proposed studies to public health is that they will provide new understanding of how proteins with expanded glutamine tracts cause neurodegeneration. This work is also expected to reveal insights into mechanisms leading to selective lower motor neuron dysfunction and death.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS055746-05
Application #
8018446
Study Section
Cell Death in Neurodegeneration Study Section (CDIN)
Program Officer
Gubitz, Amelie
Project Start
2007-03-05
Project End
2012-01-31
Budget Start
2011-02-01
Budget End
2012-01-31
Support Year
5
Fiscal Year
2011
Total Cost
$341,384
Indirect Cost
Name
University of Michigan Ann Arbor
Department
Pathology
Type
Schools of Medicine
DUNS #
073133571
City
Ann Arbor
State
MI
Country
United States
Zip Code
48109
Giorgetti, Elisa; Yu, Zhigang; Chua, Jason P et al. (2016) Rescue of Metabolic Alterations in AR113Q Skeletal Muscle by Peripheral Androgen Receptor Gene Silencing. Cell Rep 17:125-36
Rocchi, Anna; Milioto, Carmelo; Parodi, Sara et al. (2016) Glycolytic-to-oxidative fiber-type switch and mTOR signaling activation are early-onset features of SBMA muscle modified by high-fat diet. Acta Neuropathol 132:127-44
Giorgetti, Elisa; Lieberman, Andrew P (2016) Polyglutamine androgen receptor-mediated neuromuscular disease. Cell Mol Life Sci 73:3991-9
Chua, Jason P; Reddy, Satya L; Yu, Zhigang et al. (2015) Disrupting SUMOylation enhances transcriptional function and ameliorates polyglutamine androgen receptor-mediated disease. J Clin Invest 125:831-45
Rusmini, Paola; Polanco, Maria Josefa; Cristofani, Riccardo et al. (2015) Aberrant Autophagic Response in The Muscle of A Knock-in Mouse Model of Spinal and Bulbar Muscular Atrophy. Sci Rep 5:15174
Pratt, William B; Gestwicki, Jason E; Osawa, Yoichi et al. (2015) Targeting Hsp90/Hsp70-based protein quality control for treatment of adult onset neurodegenerative diseases. Annu Rev Pharmacol Toxicol 55:353-71
Pratt, William B; Morishima, Yoshihiro; Gestwicki, Jason E et al. (2014) A model in which heat shock protein 90 targets protein-folding clefts: rationale for a new approach to neuroprotective treatment of protein folding diseases. Exp Biol Med (Maywood) 239:1405-13
Chua, Jason P; Reddy, Satya L; Merry, Diane E et al. (2014) Transcriptional activation of TFEB/ZKSCAN3 target genes underlies enhanced autophagy in spinobulbar muscular atrophy. Hum Mol Genet 23:1376-86
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
Lieberman, Andrew P; Yu, Zhigang; Murray, Sue et al. (2014) Peripheral androgen receptor gene suppression rescues disease in mouse models of spinal and bulbar muscular atrophy. Cell Rep 7:774-84

Showing the most recent 10 out of 18 publications