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Spinocerebellar ataxia type 13 mutation that is associated with disease onset in infancy disrupts axonal pathfinding during neuronal development.

ABSTRACT: Spinocerebellar ataxia type 13 (SCA13) is an autosomal dominant disease caused by mutations in the Kv3.3 voltage-gated potassium (K(+)) channel. SCA13 exists in two forms: infant onset is characterized by severe cerebellar atrophy, persistent motor deficits and intellectual disability, whereas adult onset is characterized by progressive ataxia and progressive cerebellar degeneration. To test the hypothesis that infant- and adult-onset mutations have differential effects on neuronal development that contribute to the age at which SCA13 emerges, we expressed wild-type Kv3.3 or infant- or adult-onset mutant proteins in motor neurons in the zebrafish spinal cord. We characterized the development of CaP (caudal primary) motor neurons at ?36 and ?48 hours post-fertilization using confocal microscopy and 3D digital reconstruction. Exogenous expression of wild-type Kv3.3 had no significant effect on CaP development. In contrast, CaP neurons expressing the infant-onset mutation made frequent pathfinding errors, sending long, abnormal axon collaterals into muscle territories that are normally innervated exclusively by RoP (rostral primary) or MiP (middle primary) motor neurons. This phenotype might be directly relevant to infant-onset SCA13 because interaction with inappropriate synaptic partners might trigger cell death during brain development. Importantly, pathfinding errors were not detected in CaP neurons expressing the adult-onset mutation. However, the adult-onset mutation tended to increase the complexity of the distal axonal arbor. From these results, we speculate that infant-onset SCA13 is associated with marked changes in the development of Kv3.3-expressing cerebellar neurons, reducing their health and viability early in life and resulting in the withered cerebellum seen in affected children.

SUBMITTER: Issa FA

PROVIDER: S-EPMC3484873 | biostudies-literature | 2012 Nov

REPOSITORIES: biostudies-literature

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Spinocerebellar ataxia type 13 mutation that is associated with disease onset in infancy disrupts axonal pathfinding during neuronal development.

Issa Fadi A FA Mock Allan F AF Sagasti Alvaro A Papazian Diane M DM

Disease models & mechanisms 20120626 6

Spinocerebellar ataxia type 13 (SCA13) is an autosomal dominant disease caused by mutations in the Kv3.3 voltage-gated potassium (K(+)) channel. SCA13 exists in two forms: infant onset is characterized by severe cerebellar atrophy, persistent motor deficits and intellectual disability, whereas adult onset is characterized by progressive ataxia and progressive cerebellar degeneration. To test the hypothesis that infant- and adult-onset mutations have differential effects on neuronal development t ...[more]

PMID: 22736459

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Project description:Several genes related to mitochondrial functions have been identified as causative genes of neuropathy or ataxia. Cytochrome c oxidase assembly factor 7 (COA7) may have a role in assembling mitochondrial respiratory chain complexes that function in oxidative phosphorylation. Here we identified four unrelated patients with recessive mutations in COA7 among a Japanese case series of 1396 patients with Charcot-Marie-Tooth disease (CMT) or other inherited peripheral neuropathies, including complex forms of CMT. We also found that all four patients had characteristic neurological features of peripheral neuropathy and ataxia with cerebellar atrophy, and some patients showed leukoencephalopathy or spinal cord atrophy on MRI scans. Validated mutations were located at highly conserved residues among different species and segregated with the disease in each family. Nerve conduction studies showed axonal sensorimotor neuropathy. Sural nerve biopsies showed chronic axonal degeneration with a marked loss of large and medium myelinated fibres. An immunohistochemical assay with an anti-COA7 antibody in the sural nerve from the control patient showed the positive expression of COA7 in the cytoplasm of Schwann cells. We also observed mildly elevated serum creatine kinase levels in all patients and the presence of a few ragged-red fibres and some cytochrome c oxidase-negative fibres in a muscle biopsy obtained from one patient, which was suggestive of subclinical mitochondrial myopathy. Mitochondrial respiratory chain enzyme assay in skin fibroblasts from the three patients showed a definitive decrease in complex I or complex IV. Immunocytochemical analysis of subcellular localization in HeLa cells indicated that mutant COA7 proteins as well as wild-type COA7 were localized in mitochondria, which suggests that mutant COA7 does not affect the mitochondrial recruitment and may affect the stability or localization of COA7 interaction partners in the mitochondria. In addition, Drosophila COA7 (dCOA7) knockdown models showed rough eye phenotype, reduced lifespan, impaired locomotive ability and shortened synaptic branches of motor neurons. Our results suggest that loss-of-function COA7 mutation is responsible for the phenotype of the presented patients, and this new entity of disease would be referred to as spinocerebellar ataxia with axonal neuropathy type 3.

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Spinocerebellar ataxia type 13 mutation that is associated with disease onset in infancy disrupts axonal pathfinding during neuronal development.

Publications

Spinocerebellar ataxia type 13 mutation that is associated with disease onset in infancy disrupts axonal pathfinding during neuronal development.

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