title: PGC-1α is a male-specific disease modifier of human and experimental amyotrophic lateral sclerosis.
abstract: Amyotrophic lateral sclerosis (ALS) is a devastating, adult-onset neurodegenerative disorder of the upper and lower motor systems. It leads to paresis, muscle wasting and inevitably to death, typically within 3-5 years. However, disease onset and survival vary considerably ranging in extreme cases from a few months to several decades. The genetic and environmental factors underlying this variability are of great interest as potential therapeutic targets. In ALS, men are affected more often and have an earlier age of onset than women. This gender difference is recapitulated in transgenic rodent models, but no underlying mechanism has been elucidated. Here we report that SNPs in the brain-specific promoter region of the transcriptional co-activator PGC-1α, a master regulator of metabolism, modulate age of onset and survival in two large and independent ALS populations and this occurs in a strictly male-specific manner. In complementary animal studies, we show that deficiency of full-length (FL) Pgc-1α leads to a significantly earlier age of onset and a borderline shortened survival in male, but not in female ALS-transgenic mice. In the animal model, FL Pgc-1α-loss is associated with reduced mRNA levels of the trophic factor Vegf-A in males, but not in females. In summary, we indentify PGC-1α as a novel and clinically relevant disease modifier of human and experimental ALS and report a sex-dependent effect of PGC-1α in this neurodegenerative disorder.
authors.affiliation: Neurology, Ulm University, 89081 Ulm, Germany.
authors.forename: Judith
authors.initials: J
authors.lastname: Eschbach
authors.forename: Birgit
authors.initials: B
authors.lastname: Schwalenstöcker
authors.forename: Selma M
authors.initials: SM
authors.lastname: Soyal
authors.forename: Hanna
authors.initials: H
authors.lastname: Bayer
authors.forename: Diana
authors.initials: D
authors.lastname: Wiesner
authors.forename: Chizuru
authors.initials: C
authors.lastname: Akimoto
authors.forename: Ann-Charloth
authors.initials: AC
authors.lastname: Nilsson
authors.forename: Anna
authors.initials: A
authors.lastname: Birve
authors.forename: Thomas
authors.initials: T
authors.lastname: Meyer
authors.forename: Luc
authors.initials: L
authors.lastname: Dupuis
authors.forename: Karin M
authors.initials: KM
authors.lastname: Danzer
authors.forename: Peter M
authors.initials: PM
authors.lastname: Andersen
authors.forename: Anke
authors.initials: A
authors.lastname: Witting
authors.forename: Albert C
authors.initials: AC
authors.lastname: Ludolph
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Patsch
authors.forename: Patrick
authors.initials: P
authors.lastname: Weydt
mesh_terms: D000328:Adult; D017668:Age of Onset; D000368:Aged; D000690:Amyotrophic Lateral Sclerosis / Q000235:genetics* / Q000378:metabolism*; D000818:Animals; D004195:Disease Models, Animal; D005260:Female; D006801:Humans; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D008875:Middle Aged; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D020641:Polymorphism, Single Nucleotide; D012727:Sex Characteristics; D014157:Transcription Factors / Q000235:genetics* / Q000378:metabolism*; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics / Q000378:metabolism
chemical_list: C486497:PPARGC1A protein, human; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; C485290:Ppargc1a protein, mouse; D014157:Transcription Factors; D042461:Vascular Endothelial Growth Factor A; C467480:vascular endothelial growth factor A, mouse