#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

Dodecyl creatine ester improves cognitive function and identifies key protein drivers including KIF1A and PLCB1 in a mouse model of creatine transporter deficiency


  • ATP: A molecule that acts like a battery and fuels cellular processes
  • Creatine: A molecule that recharges the ATP battery
  • Slc8a1: A protein that helps cells absorb creatine so it can recharge ATP
  • Dodecyl creatine ester: A modified version of creatine that can supplement for creatine deficiency.

We often talk about KIF1A being a fast-walking, long-distance motor protein, but where does that energy come from? The answer for KIF1A, and thousands of other proteins in your body, is adenosine triphosphate, or ATP for short.

ATP is used by all known living organisms and it acts like a rechargeable battery – its energy is used up to fuel molecular processes like KIF1A’s movement, and it can be recharged by other molecules in your body to power the next process. One such “recharger” is creatine.

When molecules that recharge ATP like creatine run out, or can’t reach the right parts of the body, it can have drastic health consequences. Mutations in Slc8a1, a transporter that helps cells absorb creatine, is a cause of intellectual disability and autistic-like symptoms. These mice are said to have “creatine transporter deficiency”, but we’ll call them creatine deficient for short.

Past studies have found that supplementing with dodecyl creatine ester (DCE), a molecule closely related to creatine, improved cognitive symptoms in creatine deficient mice. In this week’s article, researchers tested the impact of intranasal DCE treatment on these mice, measuring their cognitive performance and changes in protein levels, including KIF1A.

Creatine deficient mice performed worse than healthy mice in cognitive assessments, but improved in response to DCE treatments. We’ll describe some of those experiments at the end of the article.

The researchers then took protein samples from various brain regions, looking for proteins that A) were different between healthy and creatine deficient mice, and B) returned to healthy levels when creatine deficient mice were treated with DCE.

They found that KIF1A was significantly upregulated by creatine deficiency – this may represent cells making excess KIF1A to compensate for motors that aren’t working. When these mice were treated with DCE, KIF1A expression dropped to healthy levels again.

This expression was also associated with increased levels of KIF1A cargo like BDNF, which plays an important role in cognition and memory.

The exact relationship between Slc8a1 and KIF1A still isn’t known – a lack of recharged ATP might directly cause KIF1A dysfunction, or Slc8a1 may act on other proteins that regulate how much KIF1A is made in the body. Follow up research might involve testing if we can improve symptoms in creatine deficient mice directly by decreasing KIF1A levels. We could also test DCE and other creatine-related molecules in our KAND models to look for potential therapeutic effects.

How do you test cognition and memory in a mouse?

Testing therapeutics in animals can be a challenge when looking for cognitive effects – a mouse can’t speak and it can’t answer test questions. But they do interact intelligently with their environment, and we can test those interactions to look for cognitive and memory deficits, and treat them. The authors of this study used three behavioral tests:

  • Object Recognition Task: Rodents tend to be interested in new features in their environment. In this test, animals were exposed to two objects and allowed to explore them. The next day, they were provided with one of the old objects, as well as a new object. The researchers then measure how long the mice spend exploring the new vs old object. This measures their memory and discrimination.
  • Y-Maze: In this test, mice are placed inside of a chamber with three hallways, spread like a letter Y. When exploring new spaces, mice tend to regularly switch hallways, while mice with cognitive or memory deficits are more likely to backtrack into the hallway they just came from.
  • Water Morris Maze: In this test, mice are placed in a swimming pool with opaque water and a hidden platform that they can stand on. The mice learn where the platform is after a few attempts, and eventually swim straight for it, whereas mice with memory problems have trouble finding the platform and spend more time swimming.

Rare Roundup

Congressional focus signals possible changes for orphan drug approval process

Getting a drug approved for use in a disease is a complicated process. Potential therapeutics must be approved by the FDA, which relies on advisory committees of experts who can review these drugs and the disease that they treat. But with only 18 advisory committees in the Center for Drug Evaluation and Research, and between 7,000 and 10,000 different rare diseases worldwide, finding relevant expertise can be a challenging bottleneck for rare disease communities seeking drug approval. In its recent Appropriations Act, Congress specifically encouraged the FDA to include more experts on advisory boards when reviewing applications for orphan drug approval. However, more specific guidance and requirements are needed to establish more representative committees for thousands of rare diseases.

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