Progress toward the development of treatment of spinal and bulbar muscular atrophy

ABSTRACT

Introduction: With greater longevity, the prevalence of neurodegenerative diseases including Alzheimer’s disease, Parkinson’s disease, and amyotrophic lateral sclerosis is increasing, but these diseases remain intractable. This is also the case for a hereditary motor neuron disease, spinal and bulbar muscular atrophy or SBMA.

Areas covered: SBMA typically affects adult males, eliciting motor deficits due to progressive loss of lower motor neurons, while females do not manifest neurological signs. It results from a CAG-trinucleotide repeat expansion in the androgen receptor or AR gene which is translated into an expanded polyglutamine tract within the encoded protein. Ligand-dependent nuclear accumulation of the mutant AR is implicated to lead to transcriptional dysregulation and subsequent defects in pivotal cellular functions, causing motor neuron death.

Expert opinion: Even though the pathogenesis has not been fully understood, recent advances especially in the dissection of pathomechanisms associated with the pathogenic AR protein and aggregates accelerate the development of potential targeted therapeutics such as administration of leuprorelin acetate, a potent luteinizing hormone-releasing hormone analog, which has been successfully tested in clinical trials. Combination therapies antagonizing causative mutant AR and its downstream targets hold promise to further open a therapeutic avenue for the establishment of disease modifying drugs for SBMA.

KEYWORDS:

• Androgen receptor
• leuprorelin
• polyglutamine disease
• proteostasis
• RNA
• spinal and bulbar muscular atrophy

Article highlights

1. Polyglutamine-protein aggregates in lower motor neurons are the pathological SBMA hallmarks, though the mechanism of vulnerability is unclear.

2. Reduced neurotrophic supports from SBMA muscle may contribute to non-cell-autonomous neurodegeneration.

3. Cytotoxicity of polyglutamine-expanded androgen receptor is instigated by its ligand, providing a clue to therapy development.

4. Potential therapeutic agents such as an LHRH agonist and antisense oligonucleotides are being developed for SBMA.

5. Toxic repeat-expanded RNAs and transneuronal propagation of pathogenic proteins are implicated as additional pathomechanisms in polyglutamine diseases.

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Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Additional information

Funding

This paper was funded by The Japan Agency for Medical Research and Development No. 15ek0109025 No. 15ek0109165, The Ministry of Education, Culture, Sports, Science, and Technology of Japan Grant-in-Aids (KAKENHI) /No. 16K15480 Grant-in-Aids (KAKENHI) /No. 26293206 Grant-in-Aids (KAKENHI) /No. 26461268 and The Naito Foundation.