#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.
Force generation of KIF1C is impaired by pathogenic mutations
KIF1A is a single member of a family of over 40 kinesin proteins, grouped into over a dozen families. While these motors behave differently, there are also many similarities. Learning how mutations in other kinesins affect their ability to transport cargo can provide us with more insight into KIF1A.
KIF1C is a member of the kinesin-3 family that shares many traits with KIF1A including hyperprocessivity, the ability to move large distances quickly along a microtubule. Mutations in KIF1C can cause hereditary spastic paraplegia, tremors, and cerebellar movement disorders. In this week’s article, researchers studied motor properties of healthy KIF1C, and KIF1C carrying disease-relevant mutations.
To study KIF1C, the authors used optical tweezers (learn more about optical tweezers here), tethering KIF1C to a microbead and seeing how it moves under load. They found that on average, KIF1C “backslips” on the microtubule once for every 4.5 steps forward it takes. During these backslips KIF1C is loosely bound to the microtubule, and will reattach before resuming its march forward.
The authors then introduced one of two disease-relevant mutations in the motor domain of KIF1C, a region that is highly conserved between kinesins. When mutant KIF1C motors were allowed to run without any cargo, they were actually quicker than healthy KIF1C! But speed isn’t everything, and mutant KIF1Cs were less likely to make it to their destination — they lacked traction and had a higher rate of falling off of the microtubule early. When these mutants were attached to cargo, including microbeads and large cell structures called mitochondria, they generated less force than their healthy counterparts.
Studies like this highlight an important consideration for kinesin and KIF1A research: A motor’s speed, strength, and traction all interact to determine how it moves, and changes that seem like improvements have to be tested in a biological context. At the end of the day, the biggest question is whether the cargo gets to where it needs to go.
Propofol attenuates kinesin-mediated axonal vesicle transport and fusion
KIF1A.ORG is always keeping an eye out for research that is relevant to the day-to-day lives of our families. Unfortunately, anesthesia is a common necessity for many, and one that can have adverse effects.
A study published this week found that a common anesthetic, propofol, can negatively impact KIF1A transport in cultured rat cells. Propofol impacted KIF1A speed, run length, and the delivery of cargo to synapses. This effect seems to broadly impact kinesins, but not other motor proteins like dyneins. Reducing KIF1A function is of particular concern for our community, so we want to communicate that we are actively looking to learn more.
What does this mean? While these studies are crucial, this experiment was performed in cultured cells, not at a clinical level. More than anything, it indicates that we need to gather more information. KIF1A.ORG will be having conversations with researchers and clinical experts to understand how this applies to human health. We also want to know more about your experiences with anesthesia, and will be reaching out soon to learn more from our KAND families.
CRISPR in Medicine: How can CRISPR tools treat – or prevent – disease?
KAND is a genetic disorder, and so it’s natural that many of our efforts, and our community’s questions, revolve around gene therapy, including CRISPR. We’ve discussed gene therapy administration in past #ScienceSaturdays, and talked about the opportunities and challenges of gene therapy in a past Community Call, but this week we’d like to let the experts take the wheel. Dr. Fyodor Urnov, a long-time leader in genome editing, has written an accessible and detailed outline of how CRISPR can be applied to study, treat, and prevent genetic disorders. We’re grateful to Dr. Urnov for creating this resource and encourage you to check it out!