title: Motor neurons with differential vulnerability to degeneration show distinct protein signatures in health and ALS.
abstract: The lethal disease amyotrophic lateral sclerosis (ALS) is characterized by the loss of somatic motor neurons. However, not all motor neurons are equally vulnerable to disease; certain groups are spared, including those in the oculomotor nucleus controlling eye movement. The reasons for this differential vulnerability remain unknown. Here we have identified a protein signature for resistant oculomotor motor neurons and vulnerable hypoglossal and spinal motor neurons in mouse and man and in health and ALS with the aim of understanding motor neuron resistance. Several proteins with implications for motor neuron resistance, including GABAA receptor α1, guanylate cyclase soluble subunit alpha-3 and parvalbumin were persistently expressed in oculomotor neurons in man and mouse. Vulnerable motor neurons displayed higher protein levels of dynein, peripherin and GABAA receptor α2, which play roles in retrograde transport and excitability, respectively. These were dynamically regulated during disease and thus could place motor neurons at an increased risk. From our analysis is it evident that oculomotor motor neurons have a distinct protein signature compared to vulnerable motor neurons in brain stem and spinal cord, which could in part explain their resistance to degeneration in ALS. Our comparison of human and mouse shows the relative conservation of signals across species and infers that transgenic SOD1G93A mice could be used to predict mechanisms of neuronal vulnerability in man.
authors.affiliation: Department of Neuroscience, Karolinska Institutet, Retzius v. 8, 171 77 Stockholm, Sweden.
authors.forename: L
authors.initials: L
authors.lastname: Comley
authors.affiliation: Department of Neuroscience, Karolinska Institutet, Retzius v. 8, 171 77 Stockholm, Sweden.
authors.forename: I
authors.initials: I
authors.lastname: Allodi
authors.affiliation: Department of Neuroscience, Karolinska Institutet, Retzius v. 8, 171 77 Stockholm, Sweden.
authors.forename: S
authors.initials: S
authors.lastname: Nichterwitz
authors.affiliation: Dino Ferrari Center, Neuroscience Section, Department of Pathophysiology and Transplantation, University of Milan, Neurology Unit, Istituto Di Ricovero e Cura a Carattere Scientifico Foundation Ca' Granda Ospedale Maggiore Policlinico, Milan 20122, Italy.
authors.forename: M
authors.initials: M
authors.lastname: Nizzardo
authors.affiliation: Dino Ferrari Center, Neuroscience Section, Department of Pathophysiology and Transplantation, University of Milan, Neurology Unit, Istituto Di Ricovero e Cura a Carattere Scientifico Foundation Ca' Granda Ospedale Maggiore Policlinico, Milan 20122, Italy.
authors.forename: C
authors.initials: C
authors.lastname: Simone
authors.affiliation: Dino Ferrari Center, Neuroscience Section, Department of Pathophysiology and Transplantation, University of Milan, Neurology Unit, Istituto Di Ricovero e Cura a Carattere Scientifico Foundation Ca' Granda Ospedale Maggiore Policlinico, Milan 20122, Italy.
authors.forename: S
authors.initials: S
authors.lastname: Corti
authors.affiliation: Department of Neuroscience, Karolinska Institutet, Retzius v. 8, 171 77 Stockholm, Sweden. Electronic address: eva.hedlund@ki.se.
authors.forename: E
authors.initials: E
authors.lastname: Hedlund
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000690:Amyotrophic Lateral Sclerosis / Q000378:metabolism* / Q000473:pathology; D000818:Animals; D000870:Anterior Horn Cells / Q000378:metabolism* / Q000473:pathology; D001933:Brain Stem / Q000378:metabolism* / Q000473:pathology; D002452:Cell Count; D004195:Disease Models, Animal; D005260:Female; D006801:Humans; D008297:Male; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008875:Middle Aged; D009046:Motor Neurons / Q000378:metabolism* / Q000473:pathology; D009410:Nerve Degeneration
keywords: amyotrophic lateral sclerosis; motor neuron; neurodegeneration; oculomotor; selective vulnerability