Study Probes Huntington’s Disease Protein’s Function in Injured Neurons

Summary: The Huntington’s disease protein huntingtin may have a role external to the neurodegenerative disease. Researchers say Huntingtin is involved in neural injury and regeneration.

Source: University at Buffalo

In a new University at Buffalo-led study, scientists propose a new role for the huntingtin protein (HTT), which causes Huntington’s disease when mutated.

A team led by UB biologist Shermali Gunawardena has been investigating HTT and its basic functions in cells called neurons for a long time. The scientists previously found that in its unmutated form, HTT regularly travels along neuronal highways called axons, both toward and away from the cell’s nucleus.

A new study builds on this past work, detailing a previously unknown role for HTT in cellular compartments that move in one direction, toward the nucleus.

The research suggests that HTT is involved in neuronal injury and regeneration — a novel discovery, says Gunawardena, PhD, associate professor of biological sciences in the UB College of Arts and Sciences.

“We are finding that HTT is packaged in different types of moving cargo within cells, and that it’s involved in so many processes. This suggests that it’s really a key protein in controlling a lot of cellular pathways that are important in cell survival. It doesn’t have just a single role, so it’s a very complex protein to understand,” Gunawardena says.

In the new paper, “We show that the huntingtin protein is involved during neuronal injury,” Gunawardena says.

“When neurons in fruit fly larvae were injured, we see that HTT moves from the injury site to the cell body. It likely carries components that are necessary for survival of the neuron toward the cell body, where the nucleus is and where proteins are made.”

Experiments suggest that this HTT package may carry signaling molecules that “are essential for activating the production of proteins needed for neuron regeneration,” Gunawardena says.

She adds that, “future studies will be needed to determine the identity of the molecules involved in the regeneration.”

The study was published on Sept. 9 in the journal Autophagy.

This shows a neuron
A new study builds on this past work, detailing a previously unknown role for HTT in cellular compartments that move in one direction, toward the nucleus. Image is in the public domain

“While many studies investigate disease mechanisms of HTT in Huntington’s disease, here we focused on investigating basic roles of HTT in neurons. By combining a variety of laboratory techniques, we were able to model a novel mechanism in which HTT helps injury signals transport back to the cell body after axonal injury,” says first author TJ Krzystek, PhD, who worked on the study as a PhD student in biological sciences at UB and is now a postdoctoral research fellow at Boston Children’s Hospital, Harvard Medical School and the National Institutes of Health.

“We have known for decades that neurons of the central nervous system exhibit poor regeneration following axonal injury,” Krzystek says.

“By investigating more unconventional proteins and pathways in the context of axonal regeneration, we can learn more about the potential causes of this problem with the goal of eventually opening up possibilities for finding and validating future candidates to target new therapies.”

Funding: The study was funded by the National Institute of Neurological Disorders and Stroke, part of the National Institutes of Health, and the BrightFocus Foundation. Individual authors received additional support through the American Society for Cell Biology’s travel award program and programs at UB including the Mark Diamond Research Fund, the Niciszewska Mucha Dissertation Fellowship, the Beverly Petterson Bishop and Charles W. Bishop Neuroscience Travel Award, the Center for Undergraduate Research and Creative Activities, and the Philip G. Miles Undergraduate Summer Research Fund.

About this genetics and neurology research news

Author: Charlotte Hsu
Source: University at Buffalo
Contact: Charlotte Hsu – University at Buffalo
Image: The image is in the public domain

Original Research: Closed access.
HTT (huntingtin) and RAB7 co-migrate retrogradely on a signaling LAMP1-containing late endosome during axonal injury” by Shermali Gunawardena et al. Autophagy


HTT (huntingtin) and RAB7 co-migrate retrogradely on a signaling LAMP1-containing late endosome during axonal injury

HTT (huntingtin) is a 350-kDa protein of unknown function. While HTT moves bidirectionally within axons and HTT loss/reduction causes axonal transport defects, the identity of cargo-containing vesicles that HTT helps move remain elusive.

Previously, we found an axonal retrogradely moving HTT-Rab7 vesicle complex; however, its biological relevance is unclear. Using Drosophila genetics, in vivo microscopy, membrane isolation and pharmacological inhibition, here we identified that adaptors Hip1 and Rilpl aid the retrograde motility of LAMP1-containing HTT-Rab7 late endosomes, not autophagosomes.

Reduction of Syx17 and chloroquine- or bafilomycin A1-mediated pharmacological inhibition, but not reduction of Atg5, disrupted the in vivo motility of these vesicles.

Further, because HTT-Rab7 vesicles colocalized with long-distance signaling components (BMP signaling: tkv-wit, injury: wnd) and move in a retrograde direction after Drosophila nerve crush, we propose that these vesicles likely traffic damage signals following axonal injury.

Together, our findings support a previously unknown role for HTT in the retrograde movement of a Rab7-LAMP1-containing signaling late endosome.

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