PLS3 Overexpression Delays Ataxia in Chp1 Mutant Mice - Kölner UniversitätsPublikationsServer

Janzen, Eva, Wolff, Lisa, Mendoza-Ferreira, Natalia, Hupperich, Kristina, Delle Vedove, Andrea, Hosseinibarkooie, Seyyedmohsen, Kye, Min Jeong and Wirth, Brunhilde ORCID: 0000-0003-4051-5191 (2019). PLS3 Overexpression Delays Ataxia in Chp1 Mutant Mice. Front. Neurosci., 13. LAUSANNE: FRONTIERS MEDIA SA. ISSN 1662-453X

Full text not available from this repository.

DOI:10.3389/fnins.2019.00993

Abstract

Many neurodegenerative disorders share common pathogenic pathways such as endocytic defects, Ca2+ misregulation and defects in actin dynamics. Factors acting on these shared pathways are highly interesting as a therapeutic target. Plastin 3 (PLS3), a proven protective modifier of spinal muscular atrophy across species, is a remarkable example of the former, and thereby offers high potential as a cross-disease modifier. Importantly, PLS3 has been linked to numerous proteins associated with various neurodegenerative diseases. Among them, PLS3 directly interacts with calcineurin like EF-hand protein 1 (CHP1), whose loss-of-function results in ataxia. In this study, we aimed to determine whether PLS3 is a cross-disease modifier for ataxia caused by Chp1 mutation in mice. For this purpose, we generated Chp1 mutant mice, named vacillator mice, overexpressing a PLS3 transgene. Here, we show that PLS3 overexpression (OE) delays the ataxic phenotype of the vacillator mice at an early but not later disease stage. Furthermore, we demonstrated that PLS3 OE ameliorates axon hypertrophy and axonal swellings in Purkinje neurons thereby slowing down neurodegeneration. Mechanistically, we found that PLS3 OE in the cerebellum shows a trend of increased membrane targeting and/or expression of Na+/H+ exchanger (NHE1), an important CHP1 binding partner and a causative gene for ataxia, when mutated in humans and mice. This data supports the hypothesis that PLS3 is a cross-disease genetic modifier for CHP1-causing ataxia and spinal muscular atrophy.

Item Type:

Journal Article

Creators:

Creators	Email	ORCID	ORCID Put Code
Janzen, Eva	UNSPECIFIED	UNSPECIFIED	UNSPECIFIED
Wolff, Lisa	UNSPECIFIED	UNSPECIFIED	UNSPECIFIED
Mendoza-Ferreira, Natalia	UNSPECIFIED	UNSPECIFIED	UNSPECIFIED
Hupperich, Kristina	UNSPECIFIED	UNSPECIFIED	UNSPECIFIED
Delle Vedove, Andrea	UNSPECIFIED	UNSPECIFIED	UNSPECIFIED
Hosseinibarkooie, Seyyedmohsen	UNSPECIFIED	UNSPECIFIED	UNSPECIFIED
Kye, Min Jeong	UNSPECIFIED	UNSPECIFIED	UNSPECIFIED
Wirth, Brunhilde	UNSPECIFIED	orcid.org/0000-0003-4051-5191	UNSPECIFIED