Title :

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

Author(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]

Journal title :

Scientific reports

Abbreviated title :

Sci Rep

Volume number :

9

Pages :

10854

Publication date :

2019-07-26

ISSN :

2045-2322

HAL domain(s) :

Sciences du Vivant [q-bio]

English abstract : [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 ...
Show more >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.Show less >

Language :

Anglais

Audience :

Internationale

Popular science :

Non

Administrative institution(s) :

CHU Lille
CNRS
Inserm
Université de Lille

Collections :

• Lille Neurosciences & Cognition (LilNCog) - U 1172

Research team(s) :

Troubles cognitifs dégénératifs et vasculaires

Submission date :

2019-11-27T14:29:45Z