Titre :

Genetic variation across rna metabolism and cell death gene networks is implicated in the semantic variant of primary progressive aphasia

Auteur(s) :

Bonham, Luke W. [Auteur]
Steele, Natasha Z R. [Auteur]
Karch, Celeste M. [Auteur]
Broce, Iris J. [Auteur]
Geier, Ethan G. [Auteur]
Wen, Natalie L. [Auteur]
Momeni, Parastoo [Auteur]
Hardy, John [Auteur]
Miller, Zachary A. [Auteur]
Gorno-Tempini, Maria Luisa [Auteur]
Hess, Christopher P. [Auteur]
Lewis, Patrick [Auteur]
Miller, Bruce L. [Auteur]
Seeley, William W. [Auteur]
Manzoni, Claudia [Auteur]
Desikan, Rahul S. [Auteur]
Baranzini, Sergio E. [Auteur]
Ferrari, Raffaele [Auteur]
Yokoyama, Jennifer S. [Auteur]

Titre de la revue :

Scientific reports

Nom court de la revue :

Sci Rep

Numéro :

9

Pagination :

10854

Date de publication :

2019-07-26

ISSN :

2045-2322

Discipline(s) HAL :

Sciences du Vivant [q-bio]

Résumé en anglais : [en]

The semantic variant of primary progressive aphasia (svPPA) is a clinical syndrome characterized by neurodegeneration and progressive loss of semantic knowledge. Unlike many other forms of frontotemporal lobar degeneration ...
Lire la suite >The semantic variant of primary progressive aphasia (svPPA) is a clinical syndrome characterized by neurodegeneration and progressive loss of semantic knowledge. Unlike many other forms of frontotemporal lobar degeneration (FTLD), svPPA has a highly consistent underlying pathology composed of TDP-43 (a regulator of RNA and DNA transcription metabolism). Previous genetic studies of svPPA are limited by small sample sizes and a paucity of common risk variants. Despite this, svPPA's relatively homogenous clinicopathologic phenotype makes it an ideal investigative model to examine genetic processes that may drive neurodegenerative disease. In this study, we used GWAS metadata, tissue samples from pathologically confirmed frontotemporal lobar degeneration, and in silico techniques to identify and characterize protein interaction networks associated with svPPA risk. We identified 64 svPPA risk genes that interact at the protein level. The protein pathways represented in this svPPA gene network are critical regulators of RNA metabolism and cell death, such as SMAD proteins and NOTCH1. Many of the genes in this network are involved in TDP-43 metabolism. Contrary to the conventional notion that svPPA is a clinical syndrome with few genetic risk factors, our analyses show that svPPA risk is complex and polygenic in nature. Risk for svPPA is likely driven by multiple common variants in genes interacting with TDP-43, along with cell death,x` working in combination to promote neurodegeneration.Lire moins >

Langue :

Anglais

Audience :

Internationale

Vulgarisation :

Non

Établissement(s) :

CHU Lille
CNRS
Inserm
Université de Lille

Collections :

• Lille Neurosciences & Cognition (LilNCog) - U 1172

Équipe(s) de recherche :

Troubles cognitifs dégénératifs et vasculaires

Date de dépôt :

2019-11-27T14:29:45Z