#ScienceSaturday posts share exciting scientific developments and educational resources with the KAND community. Each week, Dr. Dominique Lessard and Dr. Dylan Verden of KIF1A.ORG summarize newly published KIF1A-related research and highlight progress in rare disease research and therapeutic development.

KIF1A-Related Research

Tau Differentially Regulates the Transport of Early Endosomes and Lysosomes

We often liken KIF1A to a semi truck carrying goods along microtubule roads. But not all roads are created equal, and driving conditions can impact different vehicles differently — some trucks are made for off-roading but others need smooth pavement. The presence of objects on microtubules can impact how motor proteins move and where cargo ends up.

This week, we’re pleased to present a paper by Linda Balabanian that includes work from our own Dr. Dominique Lessard from her time in the Berger Lab at the University of Vermont. This study investigated how a protein called tau, which binds to microtubules, changes the movement of kinesins to impact cellular cargo transport.

To test how tau impacts cargo transport, the authors tracked cargo in cells with low or high levels of tau. Low levels of tau caused cargo to move toward the cell body, indicating inhibition of kinesin movement. Specifically, tau caused a reduction in KIF1A transport distance, similar to previous observations in kinesin-1.

Because tau can be altered by the addition of molecules (in this case a process called phosphorylation), the authors also tested the presence of a mutant tau that acts like it is always phosphorylated. While this mutation lessened tau inhibition of kinesin-1 movement, it further decreased KIF1A movement – these trucks handled the road conditions differently! This is an explanation for how tau can impact cargo transport in cells.

Lastly, while tau seems to bind all along the length of microtubules, it was less enriched at microtubule tips where KIF1A was present, indicating that tau and KIF1A compete for microtubule binding.

Just like it’s important to understand what kinds of road a truck can drive on safely, we need to know how KIF1A travels when microtubules are altered by proteins. This study on the impact of tau on cargo movement informs our understanding of KIF1A transport.

Rare Roundup

New study allows scientists to test therapeutics for rare disease affecting young children

The development of model systems that are relevant for disease is one of the biggest endeavors in preclinical research – no model is a perfect fit for the human context, so we need to use multiple lenses to get the best picture for understanding and treating diseases like KAND. For example, through our community advocacy and the hard work of our partners at Jackson Laboratories, we are developing new mouse models that allow us to better understand KAND progression and potential treatments.

A group at UW Madison recently tackled this in a subset of hereditary spastic paraplegia caused by mutations in a transport protein called Trk-fused gene. The researchers used CRISPR to introduce mutations to the Trk-fused gene in rats, which developed symptoms similar to children with these mutations. The researchers hope to use this to accelerate screening potential therapeutics for hereditary spastic paraplegia. 

FDA Approves New Treatment Option for Patients with ALS

On a more clinical note, the US Food and Drug Administration has recently approved a new therapeutic combination called Relyvrio for the treatment of amyotrophic lateral sclerosis (ALS), a fatal disease that impacts over 200,000 people around the world. Orally administered Relyvrio was tested in a clinical trial of 137 adult patients with ALS and found to slow decline and extend lifespan by 5-6 months. This could represent a huge relief for the many families impacted by ALS.

That being said, there is still more research to be done; a larger study on Relyvrio’s efficacy in 600 patients is currently underway in parallel to this approval, with results expected to come in next year. Relyvrio is currently priced at $158,000 per year by its developer, Amylyx Pharmaceuticals.

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