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Review
. 2019 Oct;16(4):928-947.
doi: 10.1007/s13311-019-00790-9.

Molecular Mechanisms and Therapeutics for SBMA/Kennedy's Disease

Frederick J Arnold  1 , Diane E Merry  2
Affiliations
Review

Molecular Mechanisms and Therapeutics for SBMA/Kennedy's Disease

Frederick J Arnold et al. Neurotherapeutics. 2019 Oct.

Abstract

Spinal and bulbar muscular atrophy (SBMA) is a neuromuscular disease caused by a polyglutamine (polyQ) expansion in the androgen receptor (AR). Despite the fact that the monogenic cause of SBMA has been known for nearly 3 decades, there is no effective treatment for this disease, underscoring the complexity of the pathogenic mechanisms that lead to a loss of motor neurons and muscle in SBMA patients. In the current review, we provide an overview of the system-wide clinical features of SBMA, summarize the structure and function of the AR, discuss both gain-of-function and loss-of-function mechanisms of toxicity caused by polyQ-expanded AR, and describe the cell and animal models utilized in the study of SBMA. Additionally, we summarize previously conducted clinical trials which, despite being based on positive results from preclinical studies, proved to be largely ineffective in the treatment of SBMA; nonetheless, these studies provide important insights as researchers develop the next generation of therapies.

Keywords: Polyglutamine; androgen receptor; motor neuron; neurodegenerative disease; spinal and bulbar muscular atrophy..

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Figures

Fig. 1
Fig. 1
Clinical manifestations of SBMA. Although neuromuscular dysfunction (bold) is the primary clinical feature of SBMA, system-wide disturbances have been reported. Symptoms related to androgen insensitivity, altered metabolism, and sensory neuropathy also affect the quality of life of SBMA patients
Fig. 2
Fig. 2
Schematic of the androgen receptor. Schematic representation of the androgen receptor (AR), depicting key functional domains of the protein. Shown here are the size and location of the DNA-binding domain (DBD) from amino acids 539 to 627, the hinge domain from amino acids 628 to 670, and the ligand-binding domain (LBD) from amino acids 671 to 919. Additionally, the polymorphic polyglutamine tract (polyQ) is depicted in the NTD along with the FxxLF motif, which participates in AR intra- and intermolecular amino-carboxyl (N/C) terminal interactions. The nuclear localization signal (NLS) is shown spanning amino acids 617 to 634 in the DBD and hinge regions. Also depicted are the two transactivation domains of the AR: the activation function 1 (AF-1) domain in the NTD and the activation function 2 (AF-2) domain in the LBD
See this image and copyright information in PMC

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