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

• Published in: Disease models & mechanisms 2012-11, Vol.5 (6), p.921-929
• Main Authors: Issa, Fadi A, Mock, Allan F, Sagasti, Alvaro, Papazian, Diane M
• Format: Article
• Language: English
• Subjects: Age; Age of Onset; Amino Acid Substitution - genetics; Animals; Apoptosis; Ataxia; Atrophy; Axons - metabolism; Axons - pathology; Genetic Predisposition to Disease; Humans; Hypotheses; Infant; Mice; Models, Neurological; Motor Neurons - metabolism; Motor Neurons - pathology; Mutation; Mutation - genetics; Neurogenesis - genetics; Neurons; Proteins; Shaw Potassium Channels - genetics; Shaw Potassium Channels - metabolism; Spinal cord; Spinocerebellar Ataxias - congenital; Spinocerebellar Degenerations - genetics; Synapses - pathology; Zebrafish - genetics; Zebrafish Proteins - genetics; Zebrafish Proteins - metabolism
• ISSN: 1754-8403; 1754-8411
• DOI: 10.1242/dmm.010157

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.