Skip to main content
eScholarship
Open Access Publications from the University of California

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
  • Steele, Natasha ZR
  • Karch, Celeste M
  • Broce, Iris
  • Geier, Ethan G
  • Wen, Natalie L
  • Momeni, Parastoo
  • Hardy, John
  • Miller, Zachary A
  • Gorno-Tempini, Maria Luisa
  • Hess, Christopher P
  • Lewis, Patrick
  • Miller, Bruce L
  • Seeley, William W
  • Manzoni, Claudia
  • Desikan, Rahul S
  • Baranzini, Sergio E
  • Ferrari, Raffaele
  • Yokoyama, Jennifer S
  • International FTD-Genomics Consortium (IFGC)
  • et al.
Abstract

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.

Many UC-authored scholarly publications are freely available on this site because of the UC's open access policies. Let us know how this access is important for you.

Main Content
Current View