Mutant Androgen Receptor Alternative Translation Initiation as novel strategy to block toxicity in SBMA.
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Data di Pubblicazione:
2023
Citazione:
Mutant Androgen Receptor Alternative Translation Initiation as novel strategy to block toxicity in SBMA / M. Chierichetti, R.M. Cristofani, P. Rusmini, V. Ferrari, B. Tedesco, M. Cozzi, E. Casarotto, P. Pramaggiore, V. Crippa, M. Galbiati, M. Piccolella, A. Poletti. ((Intervento presentato al convegno ISN-ESN 2023 Meeting tenutosi a Porto : 8-11 August nel 2023.
Abstract:
Spinal and Bulbar Muscular Atrophy is a neurodegenerative disease linked to a CAG repeat
expansion in the Androgen Receptor (AR) gene, which is translated into a polyglutamine tract
(polyQ) in the AR N-terminal region. ARpolyQ acquires neurotoxic properties and aggregates after
testosterone binding.
Different start codons (AUGs) are involved in AR translation. I-AUG leads to translation of a fulllength
AR (AR-B) which includes the pathogenic polyQ tract in SBMA. II-AUG is located
downstream to the CAG repeat leading to the translation of an alternative isoform named AR-A, this
isoform does not contain the neurotoxic polyQ tract.
Here we started to characterize AR-A behaviour and to develop an effective strategy to selectively
drive the AR translation from the II-AUG via antisense oligonucleotide (ASO) and a library of FDA
approved drugs blocking ARpolyQ toxicity (GOF) without causing AR loss of function (LOF).
Through analysis of AR-A expression levels, transactivation activity, aggregates formation and coexpression
of AR-A and AR-polyQ we demonstrate that depletion of the AR N-terminal region in
AR-A: i. did not affect AR-A translation and stability ii. maintained its testosterone responsiveness,
since AR-A had a lover transactivation capability compared to AR-B, but similar to ARpolyQ and
iii. lead to the reduction of aggregate formation in ARpolyQ:AR-A ratio-dependent manner.
Using a double report screening vector designed to detect different AR isoforms expression in relation
to the signal obtained we will perform ASO and drugs screening and, furthermore, we will understand
the function of AR-A homodimer and AR-A:ARpolyQ heterodimer.
Tipologia IRIS:
14 - Intervento a convegno non pubblicato
Elenco autori:
M. Chierichetti, R.M. Cristofani, P. Rusmini, V. Ferrari, B. Tedesco, M. Cozzi, E. Casarotto, P. Pramaggiore, V. Crippa, M. Galbiati, M. Piccolella, A. Poletti
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