Rod-derived Cone Viability Signaling for the Treatment of Inherited Retinal Degenerations

Research center

17 rue Moreau
75012 Paris
José-Alain Sahel

Institution

Inserm
Université Pierre et Marie Curie
CNRS
ED158
Université Pierre et Marie Curie

Laboratory

Phone: 01 53 46 25 48
UMR S 968
Labex Lifesenses

Keywords

Retinal Degeneration
Redox signaling
Gene therapy
Thioredoxin
Photoreceptors
Available to host a PhD student

Publications

Mei X, Chaffiol A, Kole C, Yang Y, Millet-Puel G, Clérin E, Aït-Ali N, Bennett J, Dalkara D, Sahel JA, Duebel J, Léveillard T. The Thioredoxin Encoded by the Rod-Derived Cone Viability Factor Gene Protects Cone Photoreceptors Against Oxidative Stress. Antioxid Redox Signal. 2016 Jun 1;24(16):909-23. doi: 10.1089/ars.2015.6509. Epub 2016 May 12.

Delyfer MN, Aït-Ali N#, Camara H#, Clérin E#, Korobelnik JF, Sahel JA, Léveillard T#. J Vis Exp. 2013 Aug 14;(78).

AMD Gene Consortium (# Léveillard T one of thye senior authors). Nat Genet. 2013 Apr;45(4):433-9, 439e1-2.

Jaillard C, Mouret A, Niepon ML, Clérin E#, Yang Y, Lee-Rivera I, Aït-Ali N#, Millet-Puel G#, Cronin T, Sedmak T, Raffelsberger W,Kinzel B, Trembleau A, Poch O, Bennett J, Wolfrum U, Lledo PM, Sahel JA, Léveillard T#. Hum Mol Genet. 2012 May 15;21(10):2298-311.

Clérin E#, Wicker N, Mohand-Saïd S, Poch O, Sahel JA, Léveillard T#. BMC Ophthalmol. 2011 Dec 20;11:38.

Delyfer MN, Raffelsberger W, Mercier D, Korobelnik JF, Gaudric A, Charteris DG, Tadayoni R, Metge F, Caputo G, Barale PO, Ripp R, Muller JD, Poch O, Sahel JA, Léveillard T#. PLoS One. 2011;6(12):e28791.

Fields of research

Neurological and psychiatric diseases

Research Theme

The identification of one of the mechanisms leading to a vision loss in patients suffering from inherited degenerative retinal disorders reveals a novel family of signaling genes involved in the regulation of trophic interactions and response to oxidative stress. It represents a potential therapy for these currently untreatable diseases. The Rod-derived Cone Viability Factor is encoded by the Nucleoredoxin-like-1 gene and the Nxnl1-/- mouse experiences a progressive loss of photoreceptor cells. This gene encodes for a trophic protein whose role is to maintain the function and consequently the viability of cone photoreceptors. Interestingly, it also encodes by differential splicing for a second protein product that has the characteristics of thioredoxin-like enzyme and protects the photoreceptors and more specifically its interacting protein partner, the TAU protein, against oxidative damage. This novel signaling pathway potentially links environmental insults to an endogenous neuroprotective response.

Team members

Najate Ait-Ali
Naomie Berdugo
Frédéric Blond
Emmanuelle Clérin
Géraldine Millet-Puel
Manuela Argentini

Lab rotation

Regulation of alternative splicing of the nucleoredoxin-like 1

Team leader: 

LEVEILLARD Thierry

Dates: 

January 2, 2018 - June 29, 2018

Application deadline: 

June 29, 2018

Period

~ Jan-March 2018

~ April-June 2018

Project

Rod-derived cone viability factor (RdCVF) is a truncatedthioredoxin protein of 109 residues, an alternative splice product ofthe nucleoredoxin-like 1 (NXNL1) gene secreted by rodphotoreceptors that prevents the loss of function and the death ofcone photoreceptors in the retina by stimulating aerobic glycolysis(Léveillard et al., Nature genetics 2004; Aït-Ali et al. Cell, 2015). Thesecond product of the NXNL1 gene, RdCVFL, is a 212 residuesthioredoxin expresses by both class of photoreceptors (Mei et al.,Antioxidants & redox signaling, 2016). It prevents damages triggeredby excess oxygen. The analysis of the human NXNL1 pre-mRNAsequence revealed a conserved RNA loop, immediatelydownstream of exon 1. This loop binds to two specific splicing factorsin vitro and is a candidate cis-acting element in intron retention.The student will participate in mini-gene reporter splicingassays of constructs delivered to the retina of the mouse usingrecombinant adeno-associated viral vectors to validate theimportance of this RNA loop for intron retention.Alternative splicing is at the evolutionary origin of the NXNL1gene as a super-thioredoxin system.

Contact

Institut de la Vision - 17, rue Moreau 75012 Paris - +33 1 53 46 25 48 - thierry.leveillard@inserm.fr

Supervisor: 

AÏT-ALI Najate