PGC-1 is a male-specific disease modifier of human and experimental amyotrophic lateral sclerosis

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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 35 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-1, 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-1 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-1-loss is associated with reduced mRNA levels of the trophic factor Vegf-A in males, but not in females. In summary, we indentify PGC-1 as a novel and clinically relevant disease modifier of human and experimental ALS and report a sex-dependent effect of PGC-1 in this neurodegenerative disorder.

Schwalenstocker, BirgitNeurology, Ulm University, Germany (författare)
Soyal, Selma M.Pharmacology, Paracelsus Medical University, Salzburg, Austria (författare)
Bayer, HannaNeurology, Ulm University, Germany (författare)
Wiesner, DianaNeurology, Ulm University, Germany (författare)
Akimoto, ChizuruUmeå universitet,Klinisk neurovetenskap(Swepub:umu)chak0009 (författare)
Nilsson, Ann-CharlothUmeå universitet,Klinisk neurovetenskap(Swepub:umu)anni0004 (författare)
Birve, AnnaUmeå universitet,Klinisk neurovetenskap(Swepub:umu)anbi0001 (författare)
Meyer, ThomasNeurology, Charité University Hospital, Berlin, Germany (författare)
Dupuis, LucINSERM, Strasbourg, France ; Faculté de Médecine, Université de Strasbourg, , France (författare)
Danzer, Karin M.Neurology, Ulm University, Germany (författare)
Andersen, Peter M.Umeå universitet,Klinisk neurovetenskap,Neurology, Ulm University, Germany(Swepub:umu)pean0001 (författare)
Witting, AnkeNeurology, Ulm University, Germany (författare)
Ludolph, Albert C.Neurology, Ulm University, Germany (författare)
Patsch, WolfgangPharmacology, Paracelsus Medical University, Salzburg, Austria (författare)
Weydt, PatrickNeurology, Ulm University, Germany (författare)
Neurology, Ulm University, GermanyPharmacology, Paracelsus Medical University, Salzburg, Austria (creator_code:org_t)

Ingår i:Human Molecular Genetics: Oxford University Press (OUP)22:17, s. 3477-34840964-69061460-2083

Av författaren/redakt...: Eschbach, Judith; Schwalenstocker, ...; Soyal, Selma M.; Bayer, Hanna; Wiesner, Diana; Akimoto, Chizuru; visa fler...; Nilsson, Ann-Cha ...; Birve, Anna; Meyer, Thomas; Dupuis, Luc; Danzer, Karin M.; Andersen, Peter ...; Witting, Anke; Ludolph, Albert ...; Patsch, Wolfgang; Weydt, Patrick; visa färre...

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