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

KIF1A-Related Research

Zn2+ decoration of microtubules arrests axonal transport and displaces tau, doublecortin, and MAP2C

When I was learning to drive my father took me to an empty county road, and told me to slam on the brakes from full speed to understand how the truck handled. After a few times I had a good idea of how long it took to stop, and what it felt like. Then he had me turn onto a gravel road and do it again. Stopping took much longer, and it was harder to handle the truck as it slid along the gravel. A few days later when it was raining, we did it again. He told me that driving isn’t just about the vehicle, it’s about the road you’re on.

The same is true for KIF1A as it “drives” – microtubules aren’t just a featureless highway, they’re covered in modifications that influence how motor proteins travel with their cargo. In this week’s article, researchers investigated how zinc on microtubules acts like a roadblock for kinesins.

Zinc is an essential element in protein biochemistry and abundant in our nervous system. Zinc concentrations inside neurons can rise as they fire, and can modulate synaptic proteins, but the many roles of zinc in neurons are still being discovered.

In this study, researchers manipulated zinc levels in hippocampal neurons while recording the transport of kinesin cargo including mitochondria, lysosomes, and dense core vesicles. In the presence of zinc these cargo slowed and stopped more often, and these effects could be reversed by removing the zinc.

Increasing zinc levels cause lysosomes (white), which break down cellular waste, to stall along axons in hippocampal neurons. Minckley et al. J Cell Biol 7 August 2023; 222 (8): e202208121.

How does zinc inhibit cargo transport? Rather than binding to kinesins directly, zinc binds to the microtubule, displacing other proteins that regulate the movement of kinesins. The authors found that while zinc stops motor movement, it doesn’t cause them to fall off the microtubule entirely. This reversible effect means that zinc levels can dynamically redistribute cargo in response to neuronal activity.

It’s important to note that much of this study focused on KIF5A; however, dense core vesicles, which are primarily transported by KIF1A, also stalled in response to zinc, indicating that zinc has more general effects on motor proteins.

How could this relate to KAND? This isn’t about zinc intake: Insufficient or excess zinc can have serious health consequences, and these experiments investigated zinc at physiological (healthy) levels, uncovering a nuanced role in trafficking motor proteins. Many KIF1A mutations impact its ability to move quickly, generate force, or stay on the microtubule, which becomes more obvious in experiments with large cargo or other resistance. Observing whether mutant KIF1A can “wait” on the microtubule when encountering road blocks like zinc may give us more insight into neuronal dysfunction in KAND.

Rare Roundup

Personalized Medicine May be the Key to Treating KIF1A-Associated Neurological Disorder (KAND)

Looking for a refresher on KIF1A and KAND? This week La Jolla Labs featured KAND in its Revealing Rare Genes blog with input from KIF1A.ORG. This article provides an excellent overview of the history and biology of KAND with a focus on therapeutic development, so we’ll let it speak for itself. A huge thank you to Perla Sandoval and Allison Brown for creating this resource.

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