The World Journal of
Biological Chemistry published another interesting Kennedy’s Disease study this
week. Below is a portion of the abstract. The entire paper can be read by
following the link below. This is preliminary research and more study is
required to determine the potential benefits and possible side effects.
Background - The
AR gene contains CAG repeats which affect receptor function, where fewer
repeats leads to increased receptor sensitivity to circulating androgens and
more repeats leads to decreased receptor sensitivity.
Identification of neuron selective androgen receptor inhibitors
World J Biol Chem. May 26, 2017; 8(2): 138-150
AIM
To identify neuron-selective androgen receptor (AR)
signaling inhibitors, which could be useful in the treatment of spinal and
bulbar muscular atrophy (SBMA), or Kennedy’s disease, a neuromuscular disorder
in which deterioration of motor neurons leads to progressive muscle weakness.
METHODS
Cell lines representing prostate, kidney, neuron, adipose,
and muscle tissue were developed that stably expressed the CFP-AR-YFP FRET
reporter. We used these cells to screen a library of small molecules for cell
type-selective AR inhibitors. Secondary screening in luciferase assays was used
to identify the best cell-type specific AR inhibitors. The mechanism of action
of a neuron-selective AR inhibitor was examined in vitro using luciferase
reporter assays, immunofluorescence microscopy, and immunoprecipitations. Rats
were treated with the most potent compound and tissue-selective AR inhibition
was examined using RT-qPCR of AR-regulated genes and immunohistochemistry.
RESULTS
We identified the thiazole class of antibiotics as compounds
able to inhibit AR signaling in a neuronal cell line but not a muscle cell
line. One of these antibiotics, thiostrepton is able to inhibit the activity of
both wild type and polyglutamine expanded AR in neuronal GT1-7 cells with
nanomolar potency. The thiazole antibiotics are known to inhibit FOXM1 activity
and accordingly, a novel FOXM1 inhibitor FDI-6 also inhibited AR activity in a
neuron-selective fashion. The selective inhibition of AR is likely indirect as
the varied structures of these compounds would not suggest that they are
competitive antagonists. Indeed, we found that FOXM1 expression correlates with
cell-type selectivity, FOXM1 co-localizes with AR in the nucleus, and that shRNA-mediated
knock down of FOXM1 reduces AR activity and thiostrepton sensitivity in a
neuronal cell line. Thiostrepton treatment reduces FOXM1 levels and the nuclear
localization of beta-catenin, a known co-activator of both FOXM1 and AR, and
reduces the association between beta-catenin and AR. Treatment of rats with
thiostrepton demonstrated AR signaling inhibition in neurons, but not muscles.
CONCLUSION
Our results suggest that thiazole antibiotics, or other inhibitors of the AR-FOXM1 axis, can
inhibit AR signaling selectively in motor neurons and may be useful in the
treatment or prevention of SBMA symptoms.
Drawing and Background
of CAG-AR - Wikipedia
Does the article above suggest that there might be a way to stop the progress of the disease? Are there side effects of the antibiotic mentioned above?
ReplyDeleteAs I mentioned at the beginning of the article. This is preliminary research. Dosage, side effects, etc. still need to be determined after further testing.
ReplyDelete