Pathogenesis and molecular targeted therapy of spinal and bulbar muscular atrophy

@article{Adachi2007PathogenesisAM,
  title={Pathogenesis and molecular targeted therapy of spinal and bulbar muscular atrophy},
  author={Hiroaki Adachi and Masahiro Waza and M. Katsuno and Fumiaki Tanaka and Manabu Doyu and Gen Sobue},
  journal={Neuropathology and Applied Neurobiology},
  year={2007},
  volume={33}
}
Spinal and bulbar muscular atrophy (SBMA) or Kennedy's disease is a motor neurone disease characterized by muscle atrophy, weakness, contraction fasciculations and bulbar involvement. SBMA mainly affects males, while females are usually asymptomatic. SBMA is caused by expansion of a polyglutamine (polyQ)‐encoding CAG trinucleotide repeat in the androgen receptor (AR) gene. AR belongs to the heat shock protein 90 (Hsp90) client protein family. The histopathologic hallmarks of SBMA are diffuse… 
Pathogenesis‐targeting therapeutics for spinal and bulbar muscular atrophy (SBMA)
TLDR
Advances in basic and clinical research on SBMA are now paving the way for clinical application of pathogenesis‐targeting therapeutics, leading to appearance of candidate drugs to treat this devastating disease: heat shock protein (HSP) inducer, Hsp90 inhibitor, and histone deacetylase inhibitor.
Muscle mitochondria dysfunctions in Spinal and Bulbar Muscular Atrophy
TLDR
For the first time, a cause-effect mechanism of nuclear accumulation of polyQ AR linked to a reduction of mitochondrial mass in the muscle from SBMA patients is shown, associated to an alteration of the mitochondrial membranes structure.
Therapeutic approaches to spinal and bulbar muscular atrophy.
Molecular Mechanisms and Therapeutics for SBMA/Kennedy’s Disease
TLDR
Previously conducted clinical trials, 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.
Mitochondrial abnormalities in spinal and bulbar muscular atrophy
TLDR
Evidence for mitochondrial dysfunction in SBMA cell and animal models is provided through indirect effects on the transcription of nuclear-encoded mitochondrial genes or through direct effects of the mutant protein on mitochondria or both, indicating possible benefit from mitochondrial therapy for SBMA.
Genistein, a natural product derived from soybeans, ameliorates polyglutamine‐mediated motor neuron disease
TLDR
It is demonstrated that dietary genistein ameliorates behavioral abnormalities, improves spinal cord and muscle pathology, and decreases the amounts of monomeric AR and high‐molecular‐weight mutant AR protein aggregates in SBMA transgenic mice.
B2 attenuates polyglutamine‐expanded androgen receptor toxicity in cell and fly models of spinal and bulbar muscular atrophy
TLDR
It is found that B2 increases the deposition of mutant AR into nuclear inclusions, without altering the ligand‐induced aggregation, expression, or subcellular distribution of the mutant protein, and reduces mutant AR toxicity in cell and fly models of SBMA.
Paeoniflorin eliminates a mutant AR via NF-YA-dependent proteolysis in spinal and bulbar muscular atrophy.
TLDR
It is demonstrated that paeoniflorin is able to enhance both the UPS and autophagy systems by upregulating the expression of NF-YA, which promotes therapeutic effects in an SBMA model.
New Targets for Therapy in Polyglutamine (polyQ) Expansion Diseases
TLDR
The polyglutamine (polyQ) repeat disorders are a family of inherited disorders characterized by progressive neurodegeneration, as well as the formation of intracellular protein aggregates, and the molecular mechanisms of repeat instability and pathogenic process are essential for the development of rational treatment of these diseases.
...
...

References

SHOWING 1-10 OF 173 REFERENCES
Sodium butyrate ameliorates phenotypic expression in a transgenic mouse model of spinal and bulbar muscular atrophy.
TLDR
The results indicate that sodium butyrate (SB), an HDAC inhibitor, is a possible therapeutic agent for SBMA and other polyQ diseases, although an appropriate dose should be determined for clinical application.
CHIP Overexpression Reduces Mutant Androgen Receptor Protein and Ameliorates Phenotypes of the Spinal and Bulbar Muscular Atrophy Transgenic Mouse Model
TLDR
It is demonstrated that transient overexpression of CHIP in a neuronal cell model reduces the monomeric mutant AR more effectively than it does the wild type, suggesting that the mutant AR is more sensitive to CHIP than is the wildtype.
Nuclear inclusions of the androgen receptor protein in spinal and bulbar muscular atrophy
TLDR
In the motor neurons of SBMA patients, there were AR‐immunoreactive ubiquitinated nuclear inclusions that were detected by antibodies that recognize a small portion of the N terminus of the AR protein.
Mitochondrial abnormalities in spinal and bulbar muscular atrophy
TLDR
Evidence for mitochondrial dysfunction in SBMA cell and animal models is provided through indirect effects on the transcription of nuclear-encoded mitochondrial genes or through direct effects of the mutant protein on mitochondria or both, indicating possible benefit from mitochondrial therapy for SBMA.
Loss of endogenous androgen receptor protein accelerates motor neuron degeneration and accentuates androgen insensitivity in a mouse model of X-linked spinal and bulbar muscular atrophy.
TLDR
These studies indicate that SBMA disease pathogenesis, both in the nervous system and the periphery, involves two simultaneous pathways: gain-of-function misfolded protein toxicity and loss of normal protein function.
Widespread nuclear and cytoplasmic accumulation of mutant androgen receptor in SBMA patients.
Spinal and bulbar muscular atrophy (SBMA) is an inherited adult onset motor neuron disease caused by the expansion of a polyglutamine (polyQ) tract within the androgen receptor (AR), affecting only
Castration Restores Function and Neurofilament Alterations of Aged Symptomatic Males in a Transgenic Mouse Model of Spinal and Bulbar Muscular Atrophy
TLDR
Reduced levels of unphosphorylated neurofilament heavy chain (NF-H) were observed in motor neurons, suggesting a role for NF-H in SBMA neuronal dysfunction and suggesting that hormone-based therapies designed to treat SBMA patients, even with advanced disease, are likely to be effective.
...
...