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 adultonset, 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.

Proteasome-mediated Proteolysis of the Polyglutamine-expanded Androgen Receptor Is a Late Event in Spinal and Bulbar Muscular Atrophy (SBMA) Pathogenesis

“…The NI observed in mouse and cell models of SBMA as well as in SBMA autopsy material are primarily detected with antibodies directed against N-terminal portions of the AR; antibodies detecting C-terminal epitopes failed to detect NI described in early studies (4,5,7,13) (see Fig. 1A).…”

“…Receptor-We and others had previously reported that the intranuclear inclusions found within SBMA tissue and SBMA cell and animal models contain only N-terminal portions of the AR (4,5,7,13,14) as they are detected with antibodies directed against epitopes in the N-terminal region of the AR, such as AR(H280) and AR-318, but not with antibodies that detect AR epitopes in central or C-terminal regions of the AR, such as AR(441) and AR(C19) (Fig. 1A).…”

“…Fast Migrating Species Contain Ubiquitin-Previous studies have shown the presence of ubiquitin and other proteasomal components associated with inclusions of polyglutamine-expanded AR in models of SBMA (7,13,18,34,35). If the fast migrating species represent inclusions or an inclusion-associated aggregation species, we would expect these species to be ubiquitinated.…”

“…6). The gender specificity of SBMA is due not only to the X-linked location of the AR gene but also to the requirement for androgen binding to the mutant receptor for disease manifestation (7)(8)(9)(10). While signs of androgen insensitivity are sometimes seen in SBMA, the disease is not due to a loss of AR function but rather to a gain of a toxic property of the mutant polyglutamine-expanded androgen receptor.…”

Kennedy disease (X-linked recessive bulbospinal neuronopathy): A comprehensive review from pathophysiology to therapy

“…Evidence of mixed neurogenic and myopathic processes has also been reported in mouse models of SBMA. Histopathological analysis of muscle tissues from transgenic and knock-in mice expressing polyQ-AR revealed both neurogenic and myopathic features [59] [49] [60] [33]. It is noteworthy that in the knock-in mouse model of SBMA, muscle pathology is evident prior to the onset of spinal cord pathology [61]; strongly supporting the view that muscle is a primary target of polyQ-AR toxicity [62].…”