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Interaction of Amyotrophic Lateral Sclerosis (ALS)-related Mutant Copper-Zinc Superoxide Dismutase with the Dynein-Dynactin Complex Contributes to Inclusion FormationS
An important consequence of protein misfolding related to neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS), is the formation of proteinaceous inclusions or aggregates within the central nervous system. We have previously shown that several familial ALS-linked copper-zinc sup...
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Published in: | The Journal of biological chemistry 2008-08, Vol.283 (33), p.22795-22805 |
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Main Authors: | , , , , , , |
Format: | Article |
Language: | English |
Subjects: | |
Online Access: | Get full text |
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Summary: | An important consequence of protein misfolding related to neurodegenerative
diseases, including amyotrophic lateral sclerosis (ALS), is the formation of
proteinaceous inclusions or aggregates within the central nervous system. We
have previously shown that several familial ALS-linked copper-zinc superoxide
dismutase (SOD1) mutants (A4V, G85R, and G93A) interact and co-localize with
the dynein-dynactin complex in cultured cells and affected tissues of ALS
mice. In this study, we report that the interaction between mutant SOD1 and
the dynein motor plays a critical role in the formation of large inclusions
containing mutant SOD1. Disruption of the motor by overexpression of the p50
subunit of dynactin in neuronal and non-neuronal cell cultures abolished the
association between aggregation-prone SOD1 mutants and the dynein-dynactin
complex. The p50 overexpression also prevented mutant SOD1 inclusion formation
and improved the survival of cells expressing A4V SOD1. Furthermore, we
observed that two ALS-linked SOD1 mutants, H46R and H48Q, which showed a lower
propensity to interact with the dynein motor, also produced less aggregation
and fewer large inclusions. Overall, these data suggest that formation of
large inclusions depends upon association of the abnormal SOD1s with the
dynein motor. Whether the misfolded SOD1s directly perturb axonal transport or
impair other functional properties of the dynein motor, this interaction could
propagate a toxic effect that ultimately causes motor neuron death in ALS. |
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ISSN: | 0021-9258 1083-351X |
DOI: | 10.1074/jbc.M800276200 |