title: Castration restores function and neurofilament alterations of aged symptomatic males in a transgenic mouse model of spinal and bulbar muscular atrophy.
abstract: Transgenic models of neurodegenerative disease have proved uniquely powerful for delineating pathways of neuronal dysfunction and cell death. We have developed a transgenic model of the polyglutamine disease spinal and bulbar muscular atrophy (SBMA), an adult-onset, slowly progressive motor neuron disease caused by polyglutamine expansion in the androgen receptor (AR). Mice bearing a human AR with 112 glutamines reproduce many aspects of SBMA, including slowly progressive, gender-specific motor deficits, and neuronal intranuclear inclusions. Despite substantial motor deficits in male AR112Q mice, no motor neuron loss was observed, indicating that neuronal dysfunction, rather than neuronal death, is central to disease. Moreover, reduced levels of unphosphorylated neurofilament heavy chain (NF-H) were observed in motor neurons, suggesting a role for NF-H in SBMA neuronal dysfunction. The elimination of androgens by surgical castration of severely affected, aged 112Q male mice partially restored motor function as well as NF-H levels. These data suggest that hormone-based therapies designed to treat SBMA patients, even with advanced disease, are likely to be effective.
authors.affiliation: Department of Biochemistry and Molecular Pharmacology, Thomas Jefferson University, Philadelphia, Pennsylvania 19107, USA.
authors.forename: Erica S
authors.initials: ES
authors.lastname: Chevalier-Larsen
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: O'Brien
authors.forename: Huiyi
authors.initials: H
authors.lastname: Wang
authors.forename: Shannon C
authors.initials: SC
authors.lastname: Jenkins
authors.forename: Latia
authors.initials: L
authors.lastname: Holder
authors.forename: Andrew P
authors.initials: AP
authors.lastname: Lieberman
authors.forename: Diane E
authors.initials: DE
authors.lastname: Merry
mesh_terms: D000818:Animals; D001921:Brain / Q000473:pathology; D002369:Castration; D004195:Disease Models, Animal; D018450:Disease Progression; D006801:Humans; D007794:Lameness, Animal / Q000235:genetics; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D009043:Motor Activity / Q000235:genetics; D009046:Motor Neurons / Q000378:metabolism / Q000473:pathology; D018908:Muscle Weakness / Q000235:genetics; D020966:Muscular Disorders, Atrophic / Q000235:genetics / Q000503:physiopathology* / Q000601:surgery*; D016900:Neurofilament Proteins / Q000378:metabolism*; D010455:Peptides / Q000235:genetics; D010766:Phosphorylation; D011944:Receptors, Androgen / Q000235:genetics; D020127:Recovery of Function; D012737:Sex Factors; D013116:Spinal Cord / Q000473:pathology; D016896:Treatment Outcome
chemical_list: D016900:Neurofilament Proteins; D010455:Peptides; D011944:Receptors, Androgen; C051774:neurofilament protein H; C097188:polyglutamine