title: Marinesco-Sjögren syndrome protein SIL1 regulates motor neuron subtype-selective ER stress in ALS.
abstract: Mechanisms underlying motor neuron subtype-selective endoplasmic reticulum (ER) stress and associated axonal pathology in amyotrophic lateral sclerosis (ALS) remain unclear. Here we show that the molecular environment of the ER between motor neuron subtypes is distinct, with characteristic signatures. We identify cochaperone SIL1, mutated in Marinesco-Sjögren syndrome (MSS), as being robustly expressed in disease-resistant slow motor neurons but not in ER stress-prone fast-fatigable motor neurons. In a mouse model of MSS, we demonstrate impaired ER homeostasis in motor neurons in response to loss of SIL1 function. Loss of a single functional Sil1 allele in an ALS mouse model (SOD1-G93A) enhanced ER stress and exacerbated ALS pathology. In SOD1-G93A mice, SIL1 levels were progressively and selectively reduced in vulnerable fast-fatigable motor neurons. Mechanistically, reduction in SIL1 levels was associated with lowered excitability of fast-fatigable motor neurons, further influencing expression of specific ER chaperones. Adeno-associated virus-mediated delivery of SIL1 to familial ALS motor neurons restored ER homeostasis, delayed muscle denervation and prolonged survival.
authors.affiliation: 1] Institute of Cell Biology, University of Bern, Bern, Switzerland. [2] Graduate School for Cellular and Biomedical Sciences, University of Bern, Bern, Switzerland.
authors.forename: Audrey
authors.initials: A
authors.lastname: Filézac de L'Etang
authors.affiliation: 1] Institute of Cell Biology, University of Bern, Bern, Switzerland. [2] Graduate School for Cellular and Biomedical Sciences, University of Bern, Bern, Switzerland.
authors.forename: Niran
authors.initials: N
authors.lastname: Maharjan
authors.affiliation: Institute of Cell Biology, University of Bern, Bern, Switzerland.
authors.forename: Marisa
authors.initials: M
authors.lastname: Cordeiro Braña
authors.affiliation: 1] Institute of Cell Biology, University of Bern, Bern, Switzerland. [2] Graduate School for Cellular and Biomedical Sciences, University of Bern, Bern, Switzerland.
authors.forename: Céline
authors.initials: C
authors.lastname: Ruegsegger
authors.affiliation: Institute of Cell Biology, University of Bern, Bern, Switzerland.
authors.forename: Ruth
authors.initials: R
authors.lastname: Rehmann
authors.affiliation: Institute of Neuropathology, Rheinisch-Westfälische Technische Hochschule, Aachen University Hospital, Aachen, Germany.
authors.forename: Anand
authors.initials: A
authors.lastname: Goswami
authors.affiliation: Institute of Neuropathology, Rheinisch-Westfälische Technische Hochschule, Aachen University Hospital, Aachen, Germany.
authors.forename: Andreas
authors.initials: A
authors.lastname: Roos
authors.affiliation: Division of Neuropathology, Department of Pathology, Academic Medical Centre, Amsterdam, the Netherlands.
authors.forename: Dirk
authors.initials: D
authors.lastname: Troost
authors.affiliation: Brain Mind Institute, Ecole Polytechnique Fédérale de Lausanne, Lausanne, Switzerland.
authors.forename: Bernard L
authors.initials: BL
authors.lastname: Schneider
authors.affiliation: Institute of Neuropathology, Rheinisch-Westfälische Technische Hochschule, Aachen University Hospital, Aachen, Germany.
authors.forename: Joachim
authors.initials: J
authors.lastname: Weis
authors.affiliation: Institute of Cell Biology, University of Bern, Bern, Switzerland.
authors.forename: Smita
authors.initials: S
authors.lastname: Saxena
mesh_terms: D000690:Amyotrophic Lateral Sclerosis / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D000818:Animals; D004195:Disease Models, Animal; D004721:Endoplasmic Reticulum / Q000378:metabolism*; D059865:Endoplasmic Reticulum Stress / Q000502:physiology*; D020662:Guanine Nucleotide Exchange Factors / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D009046:Motor Neurons / Q000378:metabolism* / Q000473:pathology; D013132:Spinocerebellar Degenerations / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D013482:Superoxide Dismutase / Q000235:genetics / Q000502:physiology*
chemical_list: D020662:Guanine Nucleotide Exchange Factors; C000594797:SIL1 protein, mouse; C109415:SOD1 G93A protein; D013482:Superoxide Dismutase