Neurodegenerative disease linked to microtubules
First characterized in Quebec in 1978, autosomal recessive spastic ataxia of Charlevoix–Saguenay, or ARSACS, is a hereditary neurodegenerative disease. Symptoms such as difficulty walking often appear in early childhood and continue to progress, limiting the mobility and lifespan of those affected.
In particular, ARSACS affects the cerebellum, the region of the brain that controls motor skills. It is the second most common recessive form of ataxia, or loss of muscle coordination and movement, in the world.
No cure exists for ARSACS, but in 2000, a team at McGill University identified mutations in the protein sacsin as its cause. Developing therapeutics is a challenge, however, because researchers do not completely understand sacsin’s function. Although previously published work suggests sacsin may influence mitochondrial transport and function in neurons, its role in the cell is still unclear.
Vincent Francis, a postdoctoral fellow at McGill University, joined the laboratory of Peter McPherson because he was interested in neurodegeneration. In particular, Francis wanted to work on the understudied sacsin.
“I decided to pursue the project to understand the cellular function of sacsin, which could provide potential new therapeutic strategies for the treatment of the disease,” Francis wrote to ASBMB Today.
Previous work in the lab had focused on mitochondria, so Francis began looking at the transport of other organelles. He focused on the lysosome, the recycling center of the cell, where unwanted materials can be broken down and reused. Generally, lysosomes are clustered neatly around the nucleus. However, in cells without sacsin, lysosomes were scattered all around.
Lysosomes and other organelles are transported on microtubules. In neurons without sacsin, lysosomes move less. Based on their observations, Francis and the team hypothesized that sacsin could regulate the trafficking of cargo on microtubules.
“We assumed that sacsin could probably be functioning as an adaptor for organellar transport,” Francis wrote. “Instead, what surprised us was the ability of sacsin to bind to microtubules and to modulate microtubule dynamics.”
Microtubules are required for autolysomal reformation, a process in which new lysosomes are formed. Once again, without sacsin, cells showed a decrease in this process.
Because neurons are large, expansive cells, regulation of organelle trafficking is particularly important for their function.
This research, recently published in the Journal of Biological Chemistry, suggests sacsin is a key regulator of cellular traffic. In the future, the team hopes these results will inform research that can help identify treatments for patients with ARSACS.
Francis noted that several other neurological disorders — including Alzheimer’s disease — are associated with decreases in neuronal microtubule stability. This indicates that microtubules may be a promising therapeutic target for ARSACS and other neurodegenerative diseases.
Enjoy reading ASBMB Today?
Become a member to receive the print edition four times a year and the digital edition weekly.
Learn moreGet the latest from ASBMB Today
Enter your email address, and we’ll send you a weekly email with recent articles, interviews and more.
Latest in Science
Science highlights or most popular articles
From the journals: JLR
Fixation method to quantify brain metabolites. Belly fat and liver disease crosstalk. Stopping heart diseases in schizophrenic patients. Read about the recent JLR papers on these topics.
Does a protein hold the key to Alzheimer’s?
Researchers in Maryland and Massachusetts team up to study how SORL1 promotes tau trafficking and seeding in cells that leads to the neurodegenerative disorder.
Cracking the recipe for perfect plant-based eggs
It involves finding just the right proteins. With new ingredients and processes, the next generation of substitutes will be not just more egg-like, but potentially more nutritious.
MSU researchers leverage cryo-EM for decades-in-the-making breakthrough
Lee Kroos and Ben Orlando have reported the first high-resolution experimentally determined structures of the intramembrane protease SpolVFB.
From the Journals: MCP
Rapid and precise SARS-CoV-2 detection using mass spec. Mapping brain changes from drug addiction. Decoding plant osmotic stress response. Read about recent MCP papers on these topics.
What seems dead may not be dead
Vincent Tagliabracci will receive the Earl and Thressa Stadtman Distinguished Scientist Award at the ASBMB Annual Meeting, April 12–15 in Chicago.