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Amyotrophic lateral sclerosis-associated mutant VAPBP56s perturbs calcium homeostasis to disrupt axonal transport of mitochondria

Human Molecular Genetics, ISSN: 0964-6906, Vol: 21, Issue: 9, Page: 1979-1988
2012
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Article Description

A proline-to-serine substitution at position 56 in the gene encoding vesicle-associated membrane protein-associated protein B (VAPB; VAPBP56S) causes some dominantly inherited familial forms of motor neuron disease, including amyotrophic lateral sclerosis (ALS) type-8. Here, we show that expression of ALS mutant VAPBP56S but not wild-type VAPB in neurons selectively disrupts anterograde axonal transport of mitochondria. VAPBP56S-induced disruption of mitochondrial transport involved reductions in the frequency, velocity and persistence of anterograde mitochondrial movement. Anterograde axonal transport of mitochondria is mediated by the microtubule-based molecular motor kinesin-1. Attachment of kinesin-1 to mitochondria involves the outer mitochondrial membrane protein mitochondrial Rho GTPase-1 (Miro1) which acts as a sensor for cytosolic calcium levels ([Ca. ]c); elevated [Ca. ]c disrupts mitochondrial transport via an effect on Miro1. To gain insight into the mechanisms underlying the VAPBP56S effect on mitochondrial transport, we monitored [Ca. ]c levels in VAPBP56S-expressing neurons. Expression of VAPBP56S but not VAPB increased resting [Ca. ]c and this was associated with a reduction in the amounts of tubulin but not kinesin-1 that were associated with Miro1. Moreover, expression of a Ca. insensitive mutant of Miro1 rescued defective mitochondrial axonal transport and restored the amounts of tubulin associated with the Miro1/kinesin-1 complex to normal in VAPBP56S-expressing cells. Our results suggest that ALS mutant VAPBP56S perturbs anterograde mitochondrial axonal transport by disrupting Ca. homeostasis and effecting the Miro1/kinesin-1 interaction with tubulin. © The Author 2012. Published by Oxford University Press. All rights reserved.

Bibliographic Details

Mórotz, Gábor M; De Vos, Kurt J; Vagnoni, Alessio; Ackerley, Steven; Shaw, Christopher E; Miller, Christopher C J

Oxford University Press (OUP)

Biochemistry, Genetics and Molecular Biology; Medicine

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