title: DYNC1H1 mutation alters transport kinetics and ERK1/2-cFos signalling in a mouse model of distal spinal muscular atrophy.
abstract: Mutations in the gene encoding the heavy chain subunit (DYNC1H1) of cytoplasmic dynein cause spinal muscular atrophy with lower extremity predominance, Charcot-Marie-Tooth disease and intellectual disability. We used the legs at odd angles (Loa) (DYNC1H1(F580Y)) mouse model for spinal muscular atrophy with lower extremity predominance and a combination of live-cell imaging and biochemical assays to show that the velocity of dynein-dependent microtubule minus-end (towards the nucleus) movement of EGF and BDNF induced signalling endosomes is significantly reduced in Loa embryonic fibroblasts and motor neurons. At the same time, the number of the plus-end (towards the cell periphery) moving endosomes is increased in the mutant cells. As a result, the extracellular signal-regulated kinases (ERK) 1/2 activation and c-Fos expression are altered in both mutant cell types, but the motor neurons exhibit a strikingly abnormal ERK1/2 and c-Fos response to serum-starvation induced stress. These data highlight the cell-type specific ERK1/2 response as a possible contributory factor in the neuropathological nature of Dync1h1 mutations, despite generic aberrant kinetics in both cell types, providing an explanation for how mutations in the ubiquitously expressed DYNC1H1 cause neuron-specific disease.
authors.affiliation: 1 School of Life Sciences, University of Sussex, Falmer, Brighton, BN1 9QG, UK.
authors.forename: Caroline A
authors.initials: CA
authors.lastname: Garrett
authors.affiliation: 1 School of Life Sciences, University of Sussex, Falmer, Brighton, BN1 9QG, UK.
authors.forename: Muruj
authors.initials: M
authors.lastname: Barri
authors.affiliation: 2 Department of Neurodegenerative Disease, Institute of Neurology, University College London, Queen Square, London WC1N 3BG, UK.
authors.forename: Anna
authors.initials: A
authors.lastname: Kuta
authors.affiliation: 1 School of Life Sciences, University of Sussex, Falmer, Brighton, BN1 9QG, UK.
authors.forename: Violetta
authors.initials: V
authors.lastname: Soura
authors.affiliation: 1 School of Life Sciences, University of Sussex, Falmer, Brighton, BN1 9QG, UK.
authors.forename: Wenhan
authors.initials: W
authors.lastname: Deng
authors.affiliation: 2 Department of Neurodegenerative Disease, Institute of Neurology, University College London, Queen Square, London WC1N 3BG, UK.
authors.forename: Elizabeth M C
authors.initials: EM
authors.lastname: Fisher
authors.affiliation: 3 Sobell Department of Motor Neuroscience and Movement Disorders, Institute of Neurology, University College London, Queen Square, London WC1N 3BG, UK.
authors.forename: Giampietro
authors.initials: G
authors.lastname: Schiavo
authors.affiliation: 1 School of Life Sciences, University of Sussex, Falmer, Brighton, BN1 9QG, UK m.hafezparast@sussex.ac.uk.
authors.forename: Majid
authors.initials: M
authors.lastname: Hafezparast
mesh_terms: D000818:Animals; D019208:Brain-Derived Neurotrophic Factor / Q000378:metabolism; D002478:Cells, Cultured; D016895:Culture Media, Serum-Free / Q000494:pharmacology; D056445:Cytoplasmic Dyneins / Q000235:genetics*; D004195:Disease Models, Animal; D004622:Embryo, Mammalian; D011992:Endosomes / Q000187:drug effects / Q000378:metabolism; D004815:Epidermal Growth Factor / Q000378:metabolism; D006801:Humans; D020935:MAP Kinase Signaling System / Q000235:genetics*; D051379:Mice; D008822:Mice, Transgenic; D009046:Motor Neurons / Q000187:drug effects / Q000378:metabolism; D009134:Muscular Atrophy, Spinal / Q000235:genetics*; D009154:Mutation / Q000235:genetics*; D010749:Phosphoprotein Phosphatases / Q000378:metabolism; D021381:Protein Transport / Q000187:drug effects / Q000235:genetics; D016760:Proto-Oncogene Proteins c-fos / Q000378:metabolism*; D014162:Transfection
chemical_list: D019208:Brain-Derived Neurotrophic Factor; D016895:Culture Media, Serum-Free; C511240:DYNC1H1 protein, human; D016760:Proto-Oncogene Proteins c-fos; D004815:Epidermal Growth Factor; D010749:Phosphoprotein Phosphatases; D056445:Cytoplasmic Dyneins
keywords: ERK 1/2; Loa; cytoplasmic dynein; endosomes; motor neurons