Defective protein is a double hit for ataxia
SCA5 results from a faulty gene for {beta}-III–spectrin. The disease targets the cerebellum's Purkinje cells, which control coordination. Symptoms usually start when patients are in their 20s or 30s, and they can gradually lose the ability to walk and speak. How the mutant protein damages Purkinje cells remains uncertain. {beta}-III–spectrin stabilizes synapses, suggesting that synapse deterioration might doom the cells. But the protein also helps the adapter protein dynactin hitch cargoes to dynein motors, pointing to a disruption of intracellular transportation.
Lorenzo et al. found support for both mechanisms. They engineered fruit flies to carry a mutated {beta}-III spectrin gene from either of two human families affected with SCA5, including one descended from Abraham Lincoln's paternal grandparents (whether Lincoln himself had the disease isn't clear). Fly larvae with the mutated gene had paralyzed tails. At the neuromuscular junctions where nerves and muscles meet, the larvae showed fewer presynaptic terminals.
The researchers next tracked the movement of synaptic vesicles in axons from the animals. Vesicles from flies that made the faulty {beta}-III–spectrin were slower and more likely to change direction, and thus traveled shorter distances. Other neurodegenerative diseases, including Alzheimer's disease and amyotrophic lateral sclerosis, involve faulty transport, and the results indicate that SCA5 does too.
The two mechanisms might have a common link, the researchers suggest. The complex containing {beta}-III–spectrin, dynactin, and dynein might not just haul cargoes. At the synapse it might snag microtubules that strengthen the membrane and prevent degeneration.
Original publication: Lorenzo, D.N., et al.; J. Cell Biol. 2010.
Most read news
Topics
Organizations
Other news from the department science
Get the life science industry in your inbox
By submitting this form you agree that LUMITOS AG will send you the newsletter(s) selected above by email. Your data will not be passed on to third parties. Your data will be stored and processed in accordance with our data protection regulations. LUMITOS may contact you by email for the purpose of advertising or market and opinion surveys. You can revoke your consent at any time without giving reasons to LUMITOS AG, Ernst-Augustin-Str. 2, 12489 Berlin, Germany or by e-mail at revoke@lumitos.com with effect for the future. In addition, each email contains a link to unsubscribe from the corresponding newsletter.