Substitution p.A350V in Na⁺/Mg²⁺ exchanger SLC41A1, potentially associated with Parkinson's disease, is a gain-of-function mutation.

Parkinson's disease (PD) is a complex multifactorial ailment predetermined by the interplay of various environmental and genetic factors. Systemic and intracellular magnesium (Mg) deficiency has long been suspected to contribute to the development and progress of PD and other neurodegenerative...

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Autores principales:	Martin Kolisek, Gerhard Sponder, Lucia Mastrototaro, Alina Smorodchenko, Pierre Launay, Juergen Vormann, Monika Schweigel-Röntgen
Formato:	article
Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2013
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/9c25ce6601934adb8d9216c4ffea8bf7
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spelling	oai:doaj.org-article:9c25ce6601934adb8d9216c4ffea8bf72021-11-18T08:59:27ZSubstitution p.A350V in Na⁺/Mg²⁺ exchanger SLC41A1, potentially associated with Parkinson's disease, is a gain-of-function mutation.1932-620310.1371/journal.pone.0071096https://doaj.org/article/9c25ce6601934adb8d9216c4ffea8bf72013-01-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/pmid/23976986/pdf/?tool=EBIhttps://doaj.org/toc/1932-6203Parkinson's disease (PD) is a complex multifactorial ailment predetermined by the interplay of various environmental and genetic factors. Systemic and intracellular magnesium (Mg) deficiency has long been suspected to contribute to the development and progress of PD and other neurodegenerative diseases. However, the molecular background is unknown. Interestingly, gene SLC41A1 located in the novel PD locus PARK16 has recently been identified as being a Na⁺/Mg²⁺ exchanger (NME, Mg²⁺ efflux system), a key component of cellular magnesium homeostasis. Here, we demonstrate that the substitution p.A350V potentially associated with PD is a gain-of-function mutation that enhances a core function of SLC41A1, namely Na⁺-dependent Mg²⁺ efflux by 69±10% under our experimental conditions (10-minute incubation in high-Na⁺ (145 mM) and completely Mg²⁺-free medium). The increased efflux capacity is accompanied by an insensitivity of mutant NME to cAMP stimulation suggesting disturbed hormonal regulation and leads to a reduced proliferation rate in p.A350V compared with wt cells. We hypothesize that enhanced Mg²⁺-efflux conducted by SLC41A1 variant p.A350V might result, in the long-term, in chronic intracellular Mg²⁺-deficiency, a condition that is found in various brain regions of PD patients and that exacerbates processes triggering neuronal damage.Martin KolisekGerhard SponderLucia MastrototaroAlina SmorodchenkoPierre LaunayJuergen VormannMonika Schweigel-RöntgenPublic Library of Science (PLoS)articleMedicineRScienceQENPLoS ONE, Vol 8, Iss 8, p e71096 (2013)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Martin Kolisek Gerhard Sponder Lucia Mastrototaro Alina Smorodchenko Pierre Launay Juergen Vormann Monika Schweigel-Röntgen Substitution p.A350V in Na⁺/Mg²⁺ exchanger SLC41A1, potentially associated with Parkinson's disease, is a gain-of-function mutation.
description	Parkinson's disease (PD) is a complex multifactorial ailment predetermined by the interplay of various environmental and genetic factors. Systemic and intracellular magnesium (Mg) deficiency has long been suspected to contribute to the development and progress of PD and other neurodegenerative diseases. However, the molecular background is unknown. Interestingly, gene SLC41A1 located in the novel PD locus PARK16 has recently been identified as being a Na⁺/Mg²⁺ exchanger (NME, Mg²⁺ efflux system), a key component of cellular magnesium homeostasis. Here, we demonstrate that the substitution p.A350V potentially associated with PD is a gain-of-function mutation that enhances a core function of SLC41A1, namely Na⁺-dependent Mg²⁺ efflux by 69±10% under our experimental conditions (10-minute incubation in high-Na⁺ (145 mM) and completely Mg²⁺-free medium). The increased efflux capacity is accompanied by an insensitivity of mutant NME to cAMP stimulation suggesting disturbed hormonal regulation and leads to a reduced proliferation rate in p.A350V compared with wt cells. We hypothesize that enhanced Mg²⁺-efflux conducted by SLC41A1 variant p.A350V might result, in the long-term, in chronic intracellular Mg²⁺-deficiency, a condition that is found in various brain regions of PD patients and that exacerbates processes triggering neuronal damage.
format	article
author	Martin Kolisek Gerhard Sponder Lucia Mastrototaro Alina Smorodchenko Pierre Launay Juergen Vormann Monika Schweigel-Röntgen
author_facet	Martin Kolisek Gerhard Sponder Lucia Mastrototaro Alina Smorodchenko Pierre Launay Juergen Vormann Monika Schweigel-Röntgen
author_sort	Martin Kolisek
title	Substitution p.A350V in Na⁺/Mg²⁺ exchanger SLC41A1, potentially associated with Parkinson's disease, is a gain-of-function mutation.
title_short	Substitution p.A350V in Na⁺/Mg²⁺ exchanger SLC41A1, potentially associated with Parkinson's disease, is a gain-of-function mutation.
title_full	Substitution p.A350V in Na⁺/Mg²⁺ exchanger SLC41A1, potentially associated with Parkinson's disease, is a gain-of-function mutation.
title_fullStr	Substitution p.A350V in Na⁺/Mg²⁺ exchanger SLC41A1, potentially associated with Parkinson's disease, is a gain-of-function mutation.
title_full_unstemmed	Substitution p.A350V in Na⁺/Mg²⁺ exchanger SLC41A1, potentially associated with Parkinson's disease, is a gain-of-function mutation.
title_sort	substitution p.a350v in na⁺/mg²⁺ exchanger slc41a1, potentially associated with parkinson's disease, is a gain-of-function mutation.
publisher	Public Library of Science (PLoS)
publishDate	2013
url	https://doaj.org/article/9c25ce6601934adb8d9216c4ffea8bf7
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Substitution p.A350V in Na⁺/Mg²⁺ exchanger SLC41A1, potentially associated with Parkinson's disease, is a gain-of-function mutation.

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