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.
journal_name
Hum Mol Genetjournal_title
Human molecular geneticsauthors
Eschbach J,Schwalenstöcker B,Soyal SM,Bayer H,Wiesner D,Akimoto C,Nilsson AC,Birve A,Meyer T,Dupuis L,Danzer KM,Andersen PM,Witting A,Ludolph AC,Patsch W,Weydt Pdoi
10.1093/hmg/ddt202subject
Has Abstractpub_date
2013-09-01 00:00:00pages
3477-84issue
17eissn
0964-6906issn
1460-2083pii
ddt202journal_volume
22pub_type
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