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Published on: September 21, 2021
B2 attenuates polyglutamine-expanded androgen receptor toxicity in cell and fly models of spinal and bulbar muscular
Isabella Palazzolo1, Natalia B Nedelsky, Caitlin E Askew
1Neurogenetics Branch, NINDS, NIH, Bethesda, MD, USA.
Abstract:
Expanded polyglutamine tracts cause neurodegeneration through a toxic gain-of-function mechanism. Generation of inclusions is a common feature of polyglutamine diseases and other protein misfolding disorders. Inclusion formation is likely to be a defensive response of the cell to the presence of unfolded protein. Recently, the compound B2 has been shown to increase inclusion formation and decrease toxicity of polyglutamine-expanded huntingtin in cultured cells. We explored the effect of B2 on spinal and bulbar muscular atrophy (SBMA). SBMA is caused by expansion of polyglutamine in the androgen receptor (AR) and is characterized by the loss of motor neurons in the brainstem and spinal cord. We 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. The effect of B2 on inclusions was associated with a decrease in AR transactivation function. We show that B2 reduces mutant AR toxicity in cell and fly models of SBMA, further supporting the idea that accumulation of polyglutamine-expanded protein into inclusions is protective. Our findings suggest B2 as a novel approach to therapy for SBMA.
Insights
The compound B2 promotes the formation of nuclear inclusions containing mutant androgen receptor (AR) in spinal and bulbar muscular atrophy (SBMA). This process reduces AR toxicity, suggesting B2 as a potential therapy for SBMA.
Area of Science:
- Neuroscience
- Molecular Biology
- Genetics
Background:
- Expanded polyglutamine tracts lead to neurodegeneration via a toxic gain-of-function mechanism.
- Inclusion body formation is a hallmark of polyglutamine diseases and protein misfolding disorders, potentially serving as a cellular defense.
- Spinal and bulbar muscular atrophy (SBMA) is a neurodegenerative disease caused by polyglutamine expansion in the androgen receptor (AR).
Purpose of the Study:
- To investigate the effect of compound B2 on spinal and bulbar muscular atrophy (SBMA) models.
- To determine if B2 influences the formation of nuclear inclusions by mutant androgen receptor (AR).
- To assess the therapeutic potential of B2 in SBMA.
Main Methods:
- Treatment of SBMA cell and fly models with compound B2.
- Analysis of mutant AR deposition into nuclear inclusions.
- Evaluation of AR transactivation function.
- Assessment of AR toxicity in cellular and animal models.
Main Results:
- Compound B2 increased the deposition of mutant AR into nuclear inclusions in SBMA models.
- B2 did not alter ligand-induced aggregation, expression, or subcellular distribution of mutant AR.
- The increase in inclusion formation by B2 was associated with decreased AR transactivation function and reduced AR toxicity.
- B2 demonstrated a protective effect against mutant AR toxicity in cell and fly models of SBMA.
Conclusions:
- Inclusion body formation of polyglutamine-expanded protein appears to be a protective cellular response.
- Compound B2 enhances inclusion formation and reduces toxicity of mutant AR in SBMA.
- B2 represents a promising therapeutic strategy for spinal and bulbar muscular atrophy.
