#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 Research

From the archives: Autoinhibition of a Neuronal Kinesin UNC-104/KIF1A Regulates the Size and Density of Synapses

It’s intuitive to think about mutations as things that stop a protein from functioning. So to fix mutations, we want the protein to be “on” more of the time, right? Not always. Proteins in our bodies are tightly regulated so they do the job they need to, when it needs doing. Just like you wouldn’t want a semi truck to make deliveries to places that don’t need it, we don’t want KIF1A to carry cargo to the wrong destinations. This week’s article addresses what regulates whether KIF1A is active vs. inactive, and what that means for the neuron.

The researchers worked in the worm model C. elegans where mutations in the arl-8 gene disrupted the delivery of synaptic cargo along axons. They found that 3 mutations in unc-104 (the worm version of KIF1A) restored this delivery. Notably these mutations occurred in different regions of KIF1A, showing multiple mechanisms of changing KIF1A activity. The fact that mutant arl-8 caused less KIF1A transport, which could be fixed by mutations in KIF1A, suggests that healthy ARL-8 releases KIF1A from inhibiting itself, like a key turning on a semi truck at the right time.

So what happens if we leave the trucks running? Under normal conditions, KIF1A will pause several times on its way down the axon—sometimes it delivers its cargo on the axon, sometimes it reverses direction, and sometimes it keeps moving toward the axon terminal. These choices are important for proper neuronal growth. Some KIF1A mutants would spend less time paused, and were less likely to reverse direction. This overactive KIF1A caused smaller, less abundant synapses. This effect was also seen when ARL-8 was overexpressed.

In finding treatments for KIF1A dysfunction, it’s important to remember that we don’t just want more KIF1A activity—we want a level of KIF1A activity that serves neurons’ needs, which is why our Research Network works so hard to better understand healthy KIF1A function.

Under normal conditions, KIF1A (UNC-104) is autoinhibited and won’t carry cargo. ARL-8 releases this inhibition, allowing KIF1A to bind to cargo like synaptic vesicles (SVs) and transport them to their proper destination. Niwa et al. Autoinhibition of a Neuronal Kinesin UNC-104/KIF1A Regulates the Size and Density of Synapses. Cell Reports

Rare Roundup

ALS is a rare disease, but challenges that patients and families encounter are familiar

Our ultimate goal as a rare disease community is to find treatments and cures for rare diseases like KAND. In light of the recent FDA Action Plan for Rare Neurodegenerative Diseases, including ALS, it’s also crucial to acknowledge that many negative impacts on quality of life are common across rare diseases. Patients enduring loss of skills, function, and independence are obvious impacts that often result in the need for 24/7 care. In Hawaii alone, an estimated 20% of adults are acting as caregivers, with an estimated $2.1 billion cost if they were to be paid for this labor. Insurance systems that only pay for strict definitions of “medically necessary” care severely underestimate the costs of ensuring proper care for loved ones.

“‘It’s really important that we figure out a way to fill those gaps,’ she said, ‘so we can provide some support and help to those people to take care of their loved ones.’

Throughout the years, Klohpin has seen countless diagnoses change lives.

She has seen families go bankrupt and caregivers quitting their jobs to take care of family.”

It’s important to share these common challenges across the rare disease community in order to make changes in health care systems that often neglect and overlook “rare” patients and families. The direct and indirect impacts on health, quality of life, personal and family finances, and the workforce all create an overwhelming need to find quality care and meaningful treatments for rare diseases like KAND.

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