B2 attenuates polyglutamine‐expanded androgen receptor toxicity in cell and fly models of spinal and bulbar muscular atrophy

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. Importantly, 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.

Protein Arginine Methyltransferase 1 and 8 Interact with FUS to Modify Its Sub-Cellular Distribution and Toxicity In Vitro and In Vivo

“…Immunofluorescence in COS1 cells was performed as previously described [34], [35]. Primary antibodies were: anti-HA (1∶200, Santa Cruz, sc-805), anti-FUS (1∶1000, A300-302A, Bethyl Labs, and sc-25540, Santa Cruz); anti-enhanced green fluorescent protein (EGFP, Roche).…”

The ubiquitin-proteasome system in neurodegenerative diseases: precipitating factor, yet part of the solution

“…Small molecules that promote the deposition of aggregation-prone proteins into IBs may also be beneficial in neurodegenerative diseases. For example, the compound B2 has been shown to increase inclusion formation of the mutant huntingtin fragment, polyQ-expanded AR, and α-synuclein, and thereby suppresses toxicity in cell and fly models (Bodner et al, 2006; Palazzolo et al, 2010). …”

Aggregation Formation in the Polyglutamine Diseases: Protection at a Cost?

“…The anti-cytotoxic effects of this compound were also demonstrated in a cell model of SBMA, in which B2 increased visible aggregate formation in the presence of the AR ligand, but did not affect the presence of high molecular weight microaggregates seen in the stacking gels of western blots under the same condition. This study also found that treatment with B2 improved the rough eye phenotype of a full-length polyglutamine-expanded AR Drosophila model, again suggesting that it could have therapeutic potential (Palazzolo et al, 2010). As a similar therapeutic approach, Ehrnhoefer et al (2006) found that Green tea polyphenol (−)-epigallocatechin-gallate (EGCG) could promote the formation of large spherical oligomers as detected by AFM and decrease the presence of more soluble oligomers, as detected by a nitrocellulose dot blot.…”