Pedal to the metal: Speeding up treatments for ALS

February 11, 2020

A therapeutic intervention for amyotrophic lateral sclerosis, better known as ALS or Lou Gehrig's disease, could be on the horizon thanks to unexpected findings by University of Arizona researchers.

ALS is the progressive degeneration of motor neurons that causes people to lose the ability to move and eventually speak, eat and breathe.

Within the neuronal cells of patients with ALS and other neurodegenerative diseases, two proteins - TDP-43 and FUS - are often found in bundles of molecular junk called aggregates, which can accumulate to deadly levels.

"It's not clear yet if TDP-43 aggregates themselves are truly toxic or a sign that things have gotten really bad in a cell, and this is its last Hail Mary trying to keep things in order," said Ross Buchan, assistant professor of molecular and cellular biology and a member of the BIO5 Institute. "These aggregates could possibly be toxic because they are trapping other useful molecules and not letting them do their job."

Buchan and his team set out to investigate how healthy cells clear harmful aggregates from the cell.

What they found was that the aggregates were being removed via endocytosis, which was surprising for two reasons. First, the textbook definition of endocytosis is a process in which proteins, nutrients and chemical signals from outside the cell are brought inside to be degraded and recycled by the lysosome. But in this case, endocytosis was working on aggregates that were already inside the cell. And second, there's already a mechanism, called autophagy, in place for recycling junk that originated from within a cell, yet endocytosis was doing what autophagy should have been doing instead.

"Autophagy - and also likely, although it's still uncertain, endocytosis - often slows as we age, and there are genes that are mutated in that pathway that are associated with some neurodegenerative diseases. So people thought the reason aggregates form when we get old, or when you have these diseases, is because that pathway isn't working very well," Buchan said.

Additionally, the accumulation of aggregates slows the endocytosis pathway further, creating a negative feedback loop within the cell.

"If we genetically or chemically impede the pathway, then the TDP-43 protein accumulates and becomes super toxic. The cool thing, as far as a therapy for ALS is concerned, is that we can also do the reverse," Buchan said. "We can make the endocytosis pathway work better by over-expressing parts of it, like putting the gas pedal down so it goes really fast. When we do that, then the TDP-43 aggregates are cleared really efficiently and it's no longer toxic."

Many of the paper's experiments were performed in yeast cells, but the general findings are likely translatable to human cells based on initial findings. Buchan called yeast "a powerful genetic tool," for understanding cellular processes, including those in human disease.

While the results from Buchan's lab are unexpected - "If I were to pull a textbook off the self, it would say endocytosis is for things that are outside the cell, not inside, so it's still pretty heretical," he said - there are other labs with data suggesting endocytosis can also clear already internalized proteins.

The next step is to determine how TPD-43 and FUS enter the endocytic pathway, and then to develop ways to make endocytosis work better in these cells.

"There are genetic ways to do that, but not chemically at the moment," Buchan said. "We think if we have a drug that inhibits the negative regulators of endocytosis, the pathway will go faster as a result. We have a couple ideas of where to start next."
-end-
The findings were published in the journal Molecular and Cellular Biology. Buchan's co-authors include undergraduate Amanda Warner, former post-doctoral fellow Guangbo Liu, graduate student Aaron Byrd, former graduate student Fen Pei, assistant research scientist Eman Basha and former lab technician Allison Buchanan.

University of Arizona

Related Science Articles from Brightsurf:

75 science societies urge the education department to base Title IX sexual harassment regulations on evidence and science
The American Educational Research Association (AERA) and the American Association for the Advancement of Science (AAAS) today led 75 scientific societies in submitting comments on the US Department of Education's proposed changes to Title IX regulations.

Science/Science Careers' survey ranks top biotech, biopharma, and pharma employers
The Science and Science Careers' 2018 annual Top Employers Survey polled employees in the biotechnology, biopharmaceutical, pharmaceutical, and related industries to determine the 20 best employers in these industries as well as their driving characteristics.

Science in the palm of your hand: How citizen science transforms passive learners
Citizen science projects can engage even children who previously were not interested in science.

Applied science may yield more translational research publications than basic science
While translational research can happen at any stage of the research process, a recent investigation of behavioral and social science research awards granted by the NIH between 2008 and 2014 revealed that applied science yielded a higher volume of translational research publications than basic science, according to a study published May 9, 2018 in the open-access journal PLOS ONE by Xueying Han from the Science and Technology Policy Institute, USA, and colleagues.

Prominent academics, including Salk's Thomas Albright, call for more science in forensic science
Six scientists who recently served on the National Commission on Forensic Science are calling on the scientific community at large to advocate for increased research and financial support of forensic science as well as the introduction of empirical testing requirements to ensure the validity of outcomes.

World Science Forum 2017 Jordan issues Science for Peace Declaration
On behalf of the coordinating organizations responsible for delivering the World Science Forum Jordan, the concluding Science for Peace Declaration issued at the Dead Sea represents a global call for action to science and society to build a future that promises greater equality, security and opportunity for all, and in which science plays an increasingly prominent role as an enabler of fair and sustainable development.

PETA science group promotes animal-free science at society of toxicology conference
The PETA International Science Consortium Ltd. is presenting two posters on animal-free methods for testing inhalation toxicity at the 56th annual Society of Toxicology (SOT) meeting March 12 to 16, 2017, in Baltimore, Maryland.

Citizen Science in the Digital Age: Rhetoric, Science and Public Engagement
James Wynn's timely investigation highlights scientific studies grounded in publicly gathered data and probes the rhetoric these studies employ.

Science/Science Careers' survey ranks top biotech, pharma, and biopharma employers
The Science and Science Careers' 2016 annual Top Employers Survey polled employees in the biotechnology, biopharmaceutical, pharmaceutical, and related industries to determine the 20 best employers in these industries as well as their driving characteristics.

Three natural science professors win TJ Park Science Fellowship
Professor Jung-Min Kee (Department of Chemistry, UNIST), Professor Kyudong Choi (Department of Mathematical Sciences, UNIST), and Professor Kwanpyo Kim (Department of Physics, UNIST) are the recipients of the Cheong-Am (TJ Park) Science Fellowship of the year 2016.

Read More: Science News and Science Current Events
Brightsurf.com is a participant in the Amazon Services LLC Associates Program, an affiliate advertising program designed to provide a means for sites to earn advertising fees by advertising and linking to Amazon.com.