Membrane Transport

Leader

Research center

45 rue des Saints Pères
75006 Paris
Daniel Zytnicki

Institution

CNRS
Université Paris Descartes

Laboratory

Neurophotonics laboratory
UMR 8250

Mots clefs

Optogenetics
Transporter
Synaptic vesicle
Lysosome
Neurodegeneration
Available to host a PhD student

publications

Chapel A, Kieffer-Jaquinod S, Sagné C#, Verdon Q#, Ivaldi C, Mellal M, Thirion J, Jadot M, Bruley C, Garin J, Gasnier B#, Journet  A (2013) An extended proteome map of the lysosomal membrane reveals novel potential transporters. Mol Cell Proteomics, 12:1572

M. Martineau, T. Shi, J. Puyal, A.M. Knolhoff, J. Dulong, B. Gasnier#, J. Klingauf, J. V. Sweedler, R. Jahn, and J-P Mothet (2013) Storage and uptake of D-serine into astrocytic synaptic-like vesicles specify gliotransmission. J Neurosci, 34:646.

A. Jezegou#, E. Llinares, C. Anne#, S. Kieffer-Jaquinod, S. O'Regan#, J. Aupetit , A. Chabli, C. Sagné#, C. Debacker#, B. Chadefaux-Vekemans, A. Journet, B. Andre, B. Gasnier# (2012) Heptahelical protein PQLC2 is a lysosomal cationic amino acid exporter underlying the action of cysteamine in cystinosis therapy. PNAS 109:E3434

R. Ruivo#, G.C. Bellenchi#, X. Chen#, G. Zifarelli, C. Sagné#, C. Debacker#, M. Pusch, S. Supplisson, B. Gasnier# (2012) Mechanism of proton/substrate coupling in the heptahelical lysosomal transporter cystinosin, PNAS 109:E210.

N. Pietrancosta*, C. Anne*#, H. Prescher, R. Ruivo#, C. Sagné#, C. Debacker#, H.O. Bertrand, R. Brossmer, F. Acher, B. Gasnier# (2012) Successful prediction of the substrate-binding pocket in the SLC17 transporter sialin, JBC 287:11489

Fields of research

Neuropharmacology / cell signaling

Research Theme

RESEARCH INTERESTS:

The nervous system is highly compartmentalized at diverse levels. At molecular level, this compartmentalization involves the sequestration and clearance of metabolites and signaling molecules into/from specific neural cell compartments. This small-molecule compartmentalization, which is performed by membrane transporters, is essential for the function and health of the nervous system. Neural cell transporters operating at the plasma membrane are well studied, especially for those involved in the extracellular clearance of neurotransmitters. In contrast, intracellular transporters are much less documented essentially for technical reasons: lesser accessibility; low affinity. Our group focuses on these intracellular proteins in the exocytic (synaptic vesicles) and endocytic (lysosomes) pathways.

VESICULAR TRANSPORTERS fill synaptic vesicles with non-peptide transmitters, a process required for, and modulating, neurotransmission.

LYSOSOMAL TRANSPORTERS export the building blocks released by the degradation of macromolecules in the endocytic, phagocytic and autophagic pathways. Thereby, they contribute to the clearance of long-lived proteins and protein aggregates, and of damaged or ageing organelles, a process essential to the maintenance of neural cells. Lysosomal transporters also contribute to metabolic homeostasis by enabling the reuse of lysosomal catabolites. In particular, they represent the final effectors in the autophagic response to nutrient starvation. Because lysosomal membrane transport still represents a significant gap in cell biology despite recent advances, we also study these proteins in non-neural cells.

 

CURRENT RESEARCH DIRECTIONS:

1) Identification and characterization of novel lysosomal transporters. We recently extended the proteomic map of the lysosomal membrane in a collaborative study. We will explore whether the recently discovered cationic amino acid transporter PQLC2 is involved in the modulation of intracellular proteolysis or the homeostasis of nitric oxide. Another protein of special interest is the putative transporter CLN7, which is defective in a juvenile form of neuronal ceroid lipofuscinosis (NCL). This group of rare diseases is characterized by an early neurodegeneration and the lysosomal accumulation of autofluorescent material (lipofuscin) in neurons and other cell types.

2) Visualization of transporter activity in live cells. We will develop fluorescent substrates of specific transporters in partnership with the group of F. Acher (Chemistry department). These compounds will provide optical probes to monitor intracellular transport processes in their native environment. These probes will be used to study the regulation of synaptic vesicle or lysosomal transport in physiological or pathophysiological context.

3) Optogenetic control of intracellular organelles. We will use light-gated modules derived from plant proteins to control the activity of specific transporters or enzymes. These tools will be used to dissect the pathogenic cascade of neurodegenerative diseases at cellular level with high spatiotemporal resolution.

Lab rotation

Cellular pathology of a neurodegenerative disease

Chercheur responsable: 

GASNIER Bruno

Dates: 

1 September 2016 - 31 December 2016

Date limite de candidature: 

1 September 2016

Lab rotation proposal:  

~ Sep-Dec 2016 ~ Jan-March 2017 ~ Apr-June 2017

Project: 

Neuronal ceroid lipofuscinoses (NCLs) are a group of rare neurodegenerative disorders characterized by blindness, epileptic seizures, motor deterioration, and dementia. We aim to investigate the hypothesis that lysosomal proteolysis is a convergent defect of NCLs using metabolomic, biochemical and cell biological approaches on cellular and mouse models.

AddressNeurophotonics laboratory- 45, rue des Saints Pères 75006 PARIS

Phone number: +33 1 70 64 99 31 ; Mailcorinne.sagne@parisdescartes.fr

Website

Superviseur: 

Corinne SAGNE