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, had the pleasure of talking with Richard McKenney, PhD, Associate Professor of Molecular and Cellular Biology at UC Davis. Dr. McKenney discusses his work dissecting the inner workings of individual KIF1A motors.

Transcript:

Dr. McKenney: My name is Richard McKenney, I’m now Associate Professor at UC Davis over here in Davis, California. I’m a graduate of Richard Vallee’s lab at Columbia University, so I feel strongly connected to the community at Columbia. I got into the molecular motors field through Richard Vallee’s work and my work in his lab, where I’ve been in the field ever since. My original works were on other types of motor proteins, but since founding my own lab in 2016, I’ve been focused on a variety of different molecular motors and KIF1A became a larger and larger part of our interest through collaborative works with multiple people, many of whom are in the KIF1A.ORG network.

Dylan: Can you describe at a broad scale what your research interests are?

Dr. McKenney: We are a biochemistry and biophysics lab, so we’re very interested in proteins. We view them as molecular machines, so we’re interested in dissecting how those machines work at an atomic or molecular level. We’re interested in the biochemical reactions that drive protein function and biophysical properties that the proteins use to perform their roles within cells. So in the case of KIF1A and kinesins in general, they’re molecular motors, meaning that they convert chemical energy from ATP hydrolysis into mechanical work, meaning they move, just like your car converts chemical energy from fuel into mechanical energy in motion. So we’re very interested in understanding what are the molecular details behind that ability, and then of course for relevance of this community, what are the consequences when something goes wrong in that process?

Dylan: What kind of model systems or assays do you use to answer those kinds of questions?

Dr. McKenney: Being a protein biochemistry lab, we are typically working in a test tube, we’re working with purified proteins, so we’re not a lab that uses mice or worms as a model system regularly, but rather we’re purifying proteins and assaying those proteins under very defined conditions. So our model system, if you will, is a biochemical reaction assay that contains the proteins that we purify and put in there. So in the case of KIF1A, we’re purifying KIF1A and its different variants and using a variety of biophysical and biochemical assays to determine how that motor works and what goes wrong with that motor when there’s different variations in the sequence.

Dylan: As somebody who’s studying KIF1A in such a direct, molecular manner, what gaps in knowledge or things would you like to address that would both help move your research forward but also help us find answers, potential therapeutics, or additional tests that we can do to better understand and treat KIF1A-Associated Neurological Disorder?

Dr. McKenney: That’s a great question. From my view, as a sort of bottom-up approach scientist if you will, I like to think about a problem as we’re not going to fully understand what’s going wrong with this motor until we can fully understand how the motor works in a normal way. So I think we still have a lot of open questions about how KIF1A moves along microtubules, what are the structural transitions in the protein organization as that molecule is working. I think along those lines in my day-to-day, so I think one of the biggest questions that remains unclear to the field is what is the structural organization, or molecular organization of the KIF1A motor? There’s been a rich history of structural biology in the KIF1A field where we have a lot of very clear atomic-level pictures of a small part of the motor, the motor domain, which is probably the most relevant, but we don’t have a good picture at all of the rest of the motor. It’s worth remembering that there’s quite a lot of protein sequence that we don’t know anything about at the structural level. So I think until we know what that looks like, we can’t form good hypotheses about how the motor works normally and also what goes wrong when there are variations in the motor’s sequence. So having an atomic-level structural detailed picture of the KIF1A motor I think would bridge a huge gap in the field for understanding how KIF1A works normally and also what goes wrong when it doesn’t.

Dylan: Are there any other thoughts as we close out that you have for the KAND, either research or patient, community?

Dr. McKenney: After being part of this community, it’s really invigorated our research, largely because of the community. Our lab focuses on several other projects that are outside of KIF1A and I can say with certainty that those projects don’t have the type of community that KIF1A has around it and that community has really strongly driven our interest level and also our drive to understand how KIF1A works, because we can see the effects and consequences of this disease on real people and real families and the feedback that I’ve received from the community has been wonderful and gracious and it’s really put a personal touch on this research project for us, and that’s the first time I’ve experienced that in almost 20 years of research now. That aspect of KIF1A research and KIF1A.ORG’s role here has been huge for us. I want to put that as a very important thought for the community that everybody who is responsible for this community is doing a great job to invigorate and inspire us researchers to push harder on what we’re doing because it’s making an impact in people’s lives. So I want to thank everybody for that.

Leave a Reply

Your email address will not be published.