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.

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.

Mutant Androgen Receptor Alternative Translation Initiation as novel strategy to block toxicity in SBMA.

M. Chierichetti
Primo
;
R.M. Cristofani
Secondo
;
P. Rusmini;V. Ferrari;B. Tedesco;M. Cozzi;E. Casarotto;P. Pramaggiore;V. Crippa;M. Galbiati;M. Piccolella
Penultimo
;
A. Poletti
Ultimo
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.
8-ago-2023
Settore BIO/13 - Biologia Applicata
International Society of Neurochemistry
European Society of Neurochemistry
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.
Conference Object
File in questo prodotto:
File Dimensione Formato  
Abstract ISN-ESN meeting_Chierichetti Marta.pdf

accesso aperto

Descrizione: Meeting abstract
Tipologia: Altro
Dimensione 84.55 kB
Formato Adobe PDF
84.55 kB Adobe PDF Visualizza/Apri
Pubblicazioni consigliate

I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.

Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/2434/1010030
Citazioni
  • ???jsp.display-item.citation.pmc??? ND
  • Scopus ND
  • ???jsp.display-item.citation.isi??? ND
social impact