Abstract
SUMMARYSpinocerebellar 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.
Highlights
Spinocerebellar ataxia type 13 (SCA13) is a human autosomal dominant disease caused by mutations in the KCNC3 gene, which encodes the Kv3.3 voltage-gated K+ channel (Waters et al, 2006)
In one form, SCA13 emerges in adulthood with progressive degeneration of the cerebellum accompanied by progressive ataxia
The authors studied the development of Kv3.3-expressing motor neurons in the zebrafish spinal cord after exogenously expressing the wild-type Kv3.3 protein, or a mutant protein associated with early-onset disease, or a mutant protein associated with late-onset disease
Summary
Spinocerebellar ataxia type 13 (SCA13) is a human autosomal dominant disease caused by mutations in the KCNC3 gene, which encodes the Kv3.3 voltage-gated K+ channel (Waters et al, 2006). SCA13 exists in distinct neurodegenerative and neurodevelopmental forms depending on which KCNC3 mutation is present (Waters et al, 2006). In one form, SCA13 emerges in adulthood with progressive degeneration of the cerebellum accompanied by progressive ataxia. In the other form, SCA13 is evident in early childhood with motor delay, persistent motor deficits and severe atrophy of the cerebellum (Herman-Bert et al, 2000). Intellectual disability and seizures have been reported in affected individuals, suggesting that infant-onset mutations detrimentally affect Kv3.3-expressing neurons outside of the cerebellum.
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