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A mutation in dynein rescues axonal transport defects and extends the lifespan of ALS mice.

journal contribution
posted on 2023-06-07, 21:28 authored by Dairin Kieran, Majid HafezparastMajid Hafezparast, Stephanie Bohnert, James R T Dick, Joanne Martin, Giampietro Schiavo, Elizabeth M C Fisher, Linda Greensmith
Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative condition characterized by motoneuron degeneration and muscle paralysis. Although the precise pathogenesis of ALS remains unclear, mutations in Cu/Zn superoxide dismutase (SOD1) account for ~2025% of familial ALS cases, and transgenic mice overexpressing human mutant SOD1 develop an ALS-like phenotype. Evidence suggests that defects in axonal transport play an important role in neurodegeneration. In Legs at odd angles (Loa) mice, mutations in the motor protein dynein are associated with axonal transport defects and motoneuron degeneration. Here, we show that retrograde axonal transport defects are already present in motoneurons of SOD1G93A mice during embryonic development. Surprisingly, crossing SOD1G93A mice with Loa/+ mice delays disease progression and significantly increases life span in Loa/SOD1G93A mice. Moreover, there is a complete recovery in axonal transport deficits in motoneurons of these mice, which may be responsible for the amelioration of disease. We propose that impaired axonal transport is a prime cause of neuronal death in neurodegenerative disorders such as ALS.

History

Publication status

  • Published

Journal

Journal of Cell Biology

ISSN

0021-9525

Issue

4

Volume

169

Page range

561-7

Pages

7.0

Department affiliated with

  • Neuroscience Publications

Notes

This paper identified retrograde axonal transport pathway as a target for delaying disease onset in motor neuron disease. MH carried out biochemical analyses of brain and spinal cords in this study. This research was a collaborative study between MH and laboratories of L. Greensmith, G. Schiavo, and E.M.C. Fisher.

Full text available

  • No

Peer reviewed?

  • Yes

Legacy Posted Date

2012-02-06

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