title: Integrated molecular landscape of amyotrophic lateral sclerosis provides insights into disease etiology.
abstract: Amyotrophic lateral sclerosis (ALS) is a severe, progressive and ultimately fatal motor neuron disease caused by a combination of genetic and environmental factors, but its underlying mechanisms are largely unknown. To gain insight into the etiology of ALS, we here conducted genetic network and literature analyses of the top-ranked findings from six genome-wide association studies of sporadic ALS (involving 3589 cases and 8577 controls) as well as genes implicated in ALS etiology through other evidence, including familial ALS candidate gene association studies. We integrated these findings into a molecular landscape of ALS that allowed the identification of three main processes that interact with each other and are crucial to maintain axonal functionality, especially of the long axons of motor neurons, i.e. (1) Rho-GTPase signaling; (2) signaling involving the three regulatory molecules estradiol, folate, and methionine; and (3) ribonucleoprotein granule functioning and axonal transport. Interestingly, estradiol signaling is functionally involved in all three cascades and as such an important mediator of the molecular ALS landscape. Furthermore, epidemiological findings together with an analysis of possible gender effects in our own cohort of sporadic ALS patients indicated that estradiol may be a protective factor, especially for bulbar-onset ALS. Taken together, our molecular landscape of ALS suggests that abnormalities within three interconnected molecular processes involved in the functioning and maintenance of motor neuron axons are important in the etiology of ALS. Moreover, estradiol appears to be an important modulator of the ALS landscape, providing important clues for the development of novel disease-modifying treatments.
authors.affiliation: Department of Molecular Animal Physiology, Donders Institute for Brain, Cognition and Behaviour, Radboud Institute for Molecular Life Sciences (RIMLS), Radboud University, Nijmegen, The Netherlands.
authors.forename: C J H M
authors.initials: CJHM
authors.lastname: Klemann
authors.affiliation: Department of Molecular Animal Physiology, Donders Institute for Brain, Cognition and Behaviour, Radboud Institute for Molecular Life Sciences (RIMLS), Radboud University, Nijmegen, The Netherlands.|Department of Neurology, Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, Nijmegen, The Netherlands.|Department of Neurology, Amphia Hospital, Breda, The Netherlands.
authors.forename: J E
authors.initials: JE
authors.lastname: Visser
authors.affiliation: Department of Neurosciences, Laboratory of Neurobiology, Experimental Neurology, KU Leuven and VIB, Vesalius Research Center, Leuven, Belgium.
authors.forename: L
authors.initials: L
authors.lastname: Van Den Bosch
authors.affiliation: Department of Molecular Animal Physiology, Donders Institute for Brain, Cognition and Behaviour, Radboud Institute for Molecular Life Sciences (RIMLS), Radboud University, Nijmegen, The Netherlands.
authors.forename: G J M
authors.initials: GJM
authors.lastname: Martens
authors.affiliation: Department of Molecular Animal Physiology, Donders Institute for Brain, Cognition and Behaviour, Radboud Institute for Molecular Life Sciences (RIMLS), Radboud University, Nijmegen, The Netherlands.|Department of Human Genetics, Radboud University Medical Center, Nijmegen, The Netherlands.
authors.forename: G
authors.initials: G
authors.lastname: Poelmans
mesh_terms: D000690:Amyotrophic Lateral Sclerosis / Q000209:etiology* / Q000235:genetics* / Q000378:metabolism; D015331:Cohort Studies; D005260:Female; D023281:Genomics; D006801:Humans; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide
keywords: amyotrophic lateral sclerosis; axonal maintenance; estradiol; etiology; molecular landscape; underlying molecular mechanisms