title: Enhanced neuronal Met signalling levels in ALS mice delay disease onset.
abstract: Signalling by receptor tyrosine kinases (RTKs) coordinates basic cellular processes during development and in adulthood. Whereas aberrant RTK signalling can lead to cancer, reactivation of RTKs is often found following stress or cell damage. This has led to the common belief that RTKs can counteract degenerative processes and so strategies to exploit them for therapy have been extensively explored. An understanding of how RTK stimuli act at cellular levels is needed, however, to evaluate their mechanism of therapeutic action. In this study, we genetically explored the biological and functional significance of enhanced signalling by the Met RTK in neurons, in the context of a neurodegenerative disease. Conditional met-transgenic mice, namely Rosa26(LacZ-stop-Met), have been engineered to trigger increased Met signalling in a temporal and tissue-specific regulated manner. Enhancing Met levels in neurons does not affect either motor neuron (MN) development or maintenance. In contrast, increased neuronal Met in amyotrophic lateral sclerosis (ALS) mice prolongs life span, retards MN loss, and ameliorates motor performance, by selectively delaying disease onset. Thus, our studies highlight the properties of RTKs to counteract toxic signals in a disease characterized by dysfunction of multiple cell types by acting in MNs. Moreover, they emphasize the relevance of genetically assessing the effectiveness of agents targeting neurons during ALS evolution.
authors.affiliation: Developmental Biology Institute of Marseille-Luminy, UMR 6216, CNRS-Inserm-Université de la Méditerranée, Campus de Luminy-Case 907, Marseille Cedex 09, France.
authors.forename: M
authors.initials: M
authors.lastname: Genestine
authors.forename: E
authors.initials: E
authors.lastname: Caricati
authors.forename: A
authors.initials: A
authors.lastname: Fico
authors.forename: S
authors.initials: S
authors.lastname: Richelme
authors.forename: H
authors.initials: H
authors.lastname: Hassani
authors.forename: C
authors.initials: C
authors.lastname: Sunyach
authors.forename: F
authors.initials: F
authors.lastname: Lamballe
authors.forename: G C
authors.initials: GC
authors.lastname: Panzica
authors.forename: B
authors.initials: B
authors.lastname: Pettmann
authors.forename: F
authors.initials: F
authors.lastname: Helmbacher
authors.forename: C
authors.initials: C
authors.lastname: Raoul
authors.forename: F
authors.initials: F
authors.lastname: Maina
authors.forename: R
authors.initials: R
authors.lastname: Dono
mesh_terms: D000690:Amyotrophic Lateral Sclerosis / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D000818:Animals; D004195:Disease Models, Animal; D005260:Female; D006801:Humans; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D009046:Motor Neurons / Q000378:metabolism* / Q000473:pathology; D019859:Proto-Oncogene Proteins c-met / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction
chemical_list: D019859:Proto-Oncogene Proteins c-met