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DYNC1H1 mutation alters transport kinetics and ERK1/2-cFos signalling in a mouse model of distal spinal muscular atrophy

journal contribution
posted on 2023-06-08, 18:23 authored by Caroline A Garrett, Muruj BarriMuruj Barri, Anna Kuta, Violetta Soura, Wenhan Deng, Elizabeth M C Fisher, Giampietro Schiavo, Majid HafezparastMajid Hafezparast
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.

Funding

Value in People Award (VIP); RA61; WELLCOME TRUST; 081431/Z/06/Z

BBSRC DRINC Training Grant 2010; G0636; BBSRC-BIOTECHNOLOGY & BIOLOGICAL SCIENCES RESEARCH COUNCIL; BB/H532032/1

Development of induced pluripotent stem (iPS) cells from mutant mouse models in order to reduce animal use; G0167; NC3RS-NAT CENT FOR REPLM, REFINM & REDUCTN OF ANIMS IN RESCH; G0900789-91302

History

Publication status

  • Published

File Version

  • Published version

Journal

Brain

ISSN

1460-2156

Publisher

Oxford University Press

Issue

7

Volume

137

Page range

1883-1893

Department affiliated with

  • Neuroscience Publications

Full text available

  • No

Peer reviewed?

  • Yes

Legacy Posted Date

2015-02-02

First Compliant Deposit (FCD) Date

2015-02-02

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