Spectrin mutations that cause spinocerebellar ataxia type 5 impair axonal transport and induce neurodegeneration in <i>Drosophila</i>

Lorenzo, Damaris N.; Li, Min-gang; Mische, Sarah; Armbrust, Karen R; Ranum, Laura P.W.; Hays, Thomas S.

doi:10.1083/jcb.200905158

Cited by 81 publications

(58 citation statements)

References 74 publications

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“…Any of these pathologies could potentially relate to gradual MT bundle decay in axons through a reduction in MT polymerization and turnover. In support of our interpretation, Spectrin-deficient neurons were shown to display axon breakage in Caenorhabditis elegans (Hammarlund et al , 2007) and cause axonal transport defects coupled to neurodegeneration in Drosophila (Lorenzo et al , 2010), and loss of Drosophila adducin or spectrin causes synapse retraction in vivo (Pielage et al , 2005, 2011). Similarly, spectraplakins as the second important promoters of MT polymerization link to the neurodegenerative disorder type IV hereditary sensory and autonomic neuropathy (OMIM ID: 614653).…”

Section: Discussionsupporting

confidence: 63%

Periodic actin structures in neuronal axons are required to maintain microtubules

Hahn

Webb

et al. 2017

MBoC

102

135

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Section: Discussionsupporting

confidence: 63%

Periodic actin structures in neuronal axons are required to maintain microtubules

Hahn

Webb

et al. 2017

MBoC

102

135

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“…An additional potential connection between Arp1 and costameres could result from interaction with β spectrin, which also is associated with costameres (4) and binds actin/Arp1 (21, 24). To test the functional significance of these interactions, we therefore determined the localization of Arp1 in skeletal muscle and its dependence on dynactin-4 and ankyrin-B.…”

Section: Resultsmentioning

confidence: 99%

Ankyrin-B Interactions with Spectrin and Dynactin-4 Are Required for Dystrophin-based Protection of Skeletal Muscle from Exercise Injury

Ayalon

Hostettler

Hoffman

et al. 2011

Journal of Biological Chemistry

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Costameres are cellular sites of mechanotransduction in heart and skeletal muscle where dystrophin and its membrane-spanning partner dystroglycan distribute intracellular contractile forces into the surrounding extracellular matrix. Resolution of a functional costamere interactome is still limited but likely to be critical for understanding forms of muscular dystrophy and cardiomyopathy. Dystrophin binds a set of membrane-associated proteins (the dystrophin-glycoprotein complex) as well as γ-actin and microtubules and also is required to align sarcolemmal microtubules with costameres. Ankyrin-B binds to dystrophin, dynactin-4, and microtubules and is required for sarcolemmal association of these proteins as well as dystroglycan. We report here that ankyrin-B interactions with β2 spectrin and dynactin-4 are required for localization of dystrophin, dystroglycan, and microtubules at costameres as well as protection of muscle from exercise-induced injury. Knockdown of dynactin-4 in adult mouse skeletal muscle phenocopied depletion of ankyrin-B and resulted in loss of sarcolemmal dystrophin, dystroglycan, and microtubules. Moreover, mutations of ankyrin-B and of dynactin-4 that selectively impaired binary interactions between these proteins resulted in loss of their costamere-localizing activity and increased muscle fiber fragility as a result of loss of costamere-associated dystrophin and dystroglycan. In addition, costamere-association of dynactin-4 did not require dystrophin but did depend on β2 spectrin and ankyrin-B, whereas costamere association of ankyrin-B required β2 spectrin. Together, these results are consistent with a functional hierarchy beginning with β2 spectrin recruitment of ankyrin-B to costameres. Ankyrin-B then interacts with dynactin-4 and dystrophin, whereas dynactin-4 collaborates with dystrophin in coordinating costamere-aligned microtubules.

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“…Genetic lesions in dynactin and the spectrin/ankyrin skeleton cause ALS and spinal cerebellar ataxia type 5 (SCA5) in humans (Puls et al, 2003; Ikeda et al, 2006). Mouse and Drosophila models of these diseases employing similar genetic lesions have been developed (LaMonte et al, 2002; Lorenzo et al, 2010). Taken together, these data imply that common cellular stresses are able to initiate motoneuron degeneration in insects and mammals.…”

Section: Introductionmentioning

confidence: 99%

Glial-Derived Prodegenerative Signaling in the Drosophila Neuromuscular System

Keller

Cheng

Locke

et al. 2011

Neuron

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SUMMARY We provide evidence for a prodegenerative, glial-derived signaling framework in the Drosophila neuromuscular system that includes caspase and mitochondria-dependent signaling. We demonstrate that Drosophila TNF-α (eiger) is expressed in a subset of peripheral glia, and the TNF-α receptor (TNFR), Wengen, is expressed in motoneurons. NMJ degeneration caused by disruption of the spectrin/ankyrin skeleton is suppressed by an eiger mutation or by eiger knockdown within a subset of peripheral glia. Loss of wengen in motoneurons causes a similar suppression providing evidence for glial-derived pro-degenerative TNF-α signaling. Neither JNK nor NFκβ is required for prodegenerative signaling. However, we provide evidence for the involvement of both an initiator and effector caspase, Dronc and Dcp-1, and mitochondrial-dependent signaling. Mutations that deplete the axon and nerve terminal of mitochondria suppress degeneration as do mutations in Drosophila Bcl-2 (debcl), a mitochondria-associated protein, and Apaf-1 (dark), which links mitochondrial signaling with caspase activity in other systems.

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Spectrin mutations that cause spinocerebellar ataxia type 5 impair axonal transport and induce neurodegeneration in Drosophila

Abstract: How spectrin mutations caused Purkinje cell death becomes clearer following studies that examined the effect of expressing mutant SCA5 in the fly eye. Mutant spectrin causes deficits in synapse formation at the neuromuscular junction and disrupts vesicular trafficking.

Cited by 81 publications

References 74 publications

Periodic actin structures in neuronal axons are required to maintain microtubules

Periodic actin structures in neuronal axons are required to maintain microtubules

Ankyrin-B Interactions with Spectrin and Dynactin-4 Are Required for Dystrophin-based Protection of Skeletal Muscle from Exercise Injury

Glial-Derived Prodegenerative Signaling in the Drosophila Neuromuscular System

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