ClC-2-like Chloride Current Alterations in a Cell Model of Spinal and Bulbar Muscular Atrophy, a Polyglutamine Disease
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ClC-2-like Chloride Current Alterations in a Cell Model of Spinal and Bulbar Muscular Atrophy, a Polyglutamine Disease Vladimir A. Martínez-Rojas 1 & Aura M. Jiménez-Garduño 1,2 & Daniela Michelatti 1,3 & Laura Tosatto 1 & Marta Marchioretto 1 & Daniele Arosio 1 & Manuela Basso 4 & Maria Pennuto 5,6,7 & Carlo Musio 1 Received: 18 May 2020 / Accepted: 14 August 2020 # Springer Science+Business Media, LLC, part of Springer Nature 2020
Abstract Spinal and bulbar muscular atrophy (SBMA) is a neuromuscular disease caused by expansions of a polyglutamine (polyQ) tract in the androgen receptor (AR) gene. SBMA is associated with the progressive loss of lower motor neurons, together with muscle weakness and atrophy. PolyQ-AR is converted to a toxic species upon binding to its natural ligands, testosterone, and dihydrotestosterone (DHT). Our previous patch-clamp studies on a motor neuron-derived cell model of SBMA showed alterations in voltage-gated ion currents. Here, we identified and characterized chloride currents most likely belonging to the chloride channel2 (ClC-2) subfamily, which showed significantly increased amplitudes in the SBMA cells. The treatment with the pituitary adenylyl cyclase-activating polypeptide (PACAP), a neuropeptide with a proven protective effect in a mouse model of SBMA, recovered chloride channel current alterations in SBMA cells. These observations suggest that the CIC-2 currents are affected in SBMA, an alteration that may contribute and potentially determine the pathophysiology of the disease. Keywords Spinal and bulbar muscular atrophy (SBMA) . PolyQ-AR cells . Patch-clamp . ClC-2 channels . Chloride currents . PACAP
Introduction Chloride (Cl−) plays an important role in regulating the excitability of neurons and muscles through changes in the membrane Vladimir A. Martínez-Rojas, Aura M. Jiménez-Garduño and Daniela Michelatti contributed equally to this work. * Carlo Musio [email protected] 1
Institute of Biophysics (IBF), Trento Unit, National Research Council (CNR) & LabSSAH, Bruno Kessler Foundation (FBK), Trento, Italy
2
Present address: Departamento de Ciencias de la Salud, Escuela de Ciencias, Universidad de las Américas Puebla (UDLAP), San Andrés Cholula, Puebla, Mexico
3
Present address: CIBIO Department, Laboratory of Chromatin Biology and Epigenetics, University of Trento, Trento, Italy
4
CIBIO Department, Laboratory of Transcriptional Neurobiology, University of Trento, Trento, Italy
5
Department of Biomedical Sciences, University of Padova, Padova, Italy
6
Padova Neuroscience Center (PNC), University of Padova, Padova, Italy
7
Veneto Institute of Molecular Medicine, Padova, Italy
potential (Arosio and Ratto 2014). In the nervous system, impaired Cl− transport is involved in, e.g., Alzheimer’s disease (De Koninck 2007), epilepsy (Huberfeld et al. 2007), neuropathic pain (Price et al. 2009), and in the regulation of synaptic inhibition in mature brain (Mahadevan and Woodin 2016). Cl− homeostasis is regulated by several proteins; among them, the largest family of p
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