AR-A IPSCS: GENERATION OF AN ADVANCED CELLULAR MODEL TO INVESTIGATE A NOVEL THERAPEUTIC APPROACH FOR SBMA
type: CreativeWork
description: Spinal and Bulbar Muscular Atrophy (SBMA) is a rare, highly disabling, neurodegenerative disease that unfortunately still lacks an effective treatment to date. Patients affected by SBMA present muscular impairment, characterized by cramps and muscle twitching in the early stages and by difficulty in swallowing and walking in the later stages, which not rarely leads to the need for a wheelchair. In addition, other systemic symptoms are present, such as sensory neuropathy, androgen insensitivity, sexual dysfunction, gynecomastia, fatty liver disease, and insulin resistance, making SBMA a disease highly impacting on patients’ life quality. SBMA is caused by an expansion of a CAG triplet repeat present in the region encoding the first exon of the androgen receptor (AR) gene, which is located on the X chromosome. SBMA is not only an X-linked inherited disease but also is dependent on levels of testosterone (T) and its active metabolite 5α-dihydrotestosterone (DHT). Physiologically, AR binds DHT, which induces a conformational change in the protein, allowing its dimerization and its translocation into the nucleus, where it acts as a transcription factor. When the CAG expansion is present, the protein presents an elongated polyQ tract (ARpolyQ). When the ARpolyQ protein interacts with DHT, only partial translocation into the nucleus occurs leading to a transcriptional loss of function (LoF), while this interaction also unmasks the polyQ tract, leading to AR toxic gain of function (GoF) and aggregation in both cytoplasm and nucleus. Given these characteristics, an ideal therapeutic approach for SBMA should reduce the ARpolyQ aggregation while maintaining its transcriptional activity. Interestingly, the AR mRNA transcript presents more than one translational start codon: in particular, an AUG (AUG-II) downstream of the CAG repeat is present, which generates a shorter isoform of the receptor called AR-A. Preliminary data from our laboratory showed that AR-A has a positive eff…
abstract: Spinal and Bulbar Muscular Atrophy (SBMA) is a rare, highly disabling, neurodegenerative disease that unfortunately still lacks an effective treatment to date. Patients affected by SBMA present muscular impairment, characterized by cramps and muscle twitching in the early stages and by difficulty in swallowing and walking in the later stages, which not rarely leads to the need for a wheelchair. In addition, other systemic symptoms are present, such as sensory neuropathy, androgen insensitivity, sexual dysfunction, gynecomastia, fatty liver disease, and insulin resistance, making SBMA a disease highly impacting on patients’ life quality. SBMA is caused by an expansion of a CAG triplet repeat present in the region encoding the first exon of the androgen receptor (AR) gene, which is located on the X chromosome. SBMA is not only an X-linked inherited disease but also is dependent on levels of testosterone (T) and its active metabolite 5α-dihydrotestosterone (DHT). Physiologically, AR binds DHT, which induces a conformational change in the protein, allowing its dimerization and its translocation into the nucleus, where it acts as a transcription factor. When the CAG expansion is present, the protein presents an elongated polyQ tract (ARpolyQ). When the ARpolyQ protein interacts with DHT, only partial translocation into the nucleus occurs leading to a transcriptional loss of function (LoF), while this interaction also unmasks the polyQ tract, leading to AR toxic gain of function (GoF) and aggregation in both cytoplasm and nucleus. Given these characteristics, an ideal therapeutic approach for SBMA should reduce the ARpolyQ aggregation while maintaining its transcriptional activity. Interestingly, the AR mRNA transcript presents more than one translational start codon: in particular, an AUG (AUG-II) downstream of the CAG repeat is present, which generates a shorter isoform of the receptor called AR-A. Preliminary data from our laboratory showed that AR-A has a positive eff…
author: PRAMAGGIORE, PAOLA
language: eng
keywords: Spinal and Bulbar Muscular Atrophy, SBMA, AR-A, androgen receptor, iPSC, induced pluripotent stem cells, differentiation, motorneuron, MN, assembled, Settore BIOS-10/A - Biologia cellulare e applicata
date published: 2025-12-15
date modified: 2026-07-27T20:19:10Z
provider: Università degli Studi di Milano
publisher: Networked Digital Library of Theses and Dissertations
type: WebPage
source organization: Università degli Studi di Milano

PropertyValue
property ID: Handle
value: https://hdl.handle.net/2434/1204319