Ahead of our 2022 Virtual KAND Family & Scientific Engagement Conference on August 13, 2022, KIF1A.ORG interviewed core KIF1A Research Network members to discuss their #relentless efforts to understand KIF1A and help KAND patients in this special “Meet the Research Network” series on the KIF1A.ORG blog.

KIF1A.ORG’s Research Engagement Director Dylan Verden, PhD, spoke with Richard Vallee, PhD, about his career of studying motor proteins including KIF1A. Dr. Vallee discusses the role of KIF1A in neurodevelopment by introducing KIF1A mutations in brain slices of rats.

Please note: this interview can be difficult to listen to or read (transcript provided below) as it discusses research that uses brains of rats with KIF1A mutations.

Transcript:

Dr. Vallee: I’m Richard Vallee, I’m at Columbia University in the Department of Pathology and Cell Biology. I’ve been here at Columbia for the past 20 years. Our research has been on what are called microtubule motor proteins. There are quite a number of them, there are many kinesins and a few dyneins. We discovered many years ago a protein called cytoplasmic dynein, which has turned out to be responsible for a pretty substantial fraction of movements in nerve cells and movements of nerve cells. A lot of our work has to do with that, and as part of our studies, we looked for other motor proteins to see if there were additional ones involved in transport and development of neuronal cells. KIF1A is one of them. So we’ve studied KIF1A for certainly more than a decade and have discovered numerous roles for KIF1A in brain development. The connection with children with mutations in the KIF1A gene is something that we’re still very interested in understanding and possibly in the far distant future, dealing with.

Dylan: When you talk about KIF1A having many roles that you’ve been coming across, what are some of those roles that have been of particular interest to you?

Dr. Vallee: KIF1A is best known to us for roles in axonal transport. In particular, transport of synaptic vesicles, which are structures that travel to the synapse in neuronal cells and are responsible for signaling between neuronal cells. A very very important role, and no doubt relevant to the problems that are associated with mutations in the KIF1A gene in people. Our own focus over the last couple of decades has been the role of these motor proteins in brain development. There were some hints that this may be the case from Orly Reiner at the Weizmann Institute in Israel working on a gene called LIS1. We found that LIS1 is a regulator of cytoplasmic dynein and that its role in brain development was closely related to the role of cytoplasmic dynein in brain development. We’ve put a lot of effort into understanding the role of LIS1 and cytoplasmic dynein in brain development, and somewhere along the way in our studies, we discovered that KIF1A was also very important in brain development and played roles that complemented those of these other proteins.

Dylan: When you’re running these experiments and making these discoveries about different motor proteins, what kind of models and techniques are you utilizing?

Dr. Vallee: One of the main approaches that we use is analysis of live post-mortem brain slices from rats. It was found a number of years ago, not by us but by many others, that it’s possible to remove brain tissue from animals like rats and mice, put them in culture the way one grows individual cells in cell culture, and we can then monitor the behavior of neuronal cells in these live rat brain slices. This was not introduced by us, initially we learned this from a collaborator then at Columbia, Arnold Kriegstein. Our contribution was to come up with ways to interfere with individual genes in these rat brain slice cultures, and we could then watch over time, by time lapse, the behavior of neuronal cells in normal rat brain versus rat brain in which we had removed or interfered with the ability to express KIF1A or cytoplasmic dynein, or in which we had introduced mutant KIF1A or cytoplasmic dynein.

Dylan: We really appreciate the scope of what you’ve been studying in terms of KIF1A function. I’d like to close out by asking if you have any final thoughts, anything that wasn’t covered in this interview that you’d like to express to our KAND community?

Dr. Vallee: One of the things that we became very excited about in the course of this work was that we found that when we interfered with or produced mutations in KIF1A and looked at the effects in rat brain slices, that there was a factor in rat brain, and of course in human brain as well, called brain-derived neurotrophic factor: BDNF. We found that very strikingly, we could restore some of the developmental defects in these rat brain in vitro slice cultures by applying BDNF. This is something that we have been pursuing. Clearly defects in brain development can be affected by applying BDNF in the brain slices. Whether BDNF has a relevance for the many other issues that arise in children with KIF1A mutations, that’s something far in the future.

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