I AM AN EMORY RESEARCHER (COPY) (COPY)

Asking important questions

ALS is a heterogeneous disease, with 10% genetic cases and 90% sporadic (meaning the cause is unknown). 

When the Ice Bucket Challenge went viral on social media a decade ago, it inspired more than 17 million people worldwide to dump ice water on their heads and donate to an ALS organization, expanding funding for ALS research and leading to the discovery of several new genes associated with the disease.

One of these is the KIF5A gene. Mutations in this gene can cause ALS, spastic paraplegia-10 and Charcot–Marie–Tooth disease. Pant received a development grant from the Muscular Dystrophy Association (MDA) to investigate the role of mutant KIF5A in ALS.

“Basically, KIF5A is a motor protein. Imagine a busy city with traffic, where cargo is being transported from one part of the city to another,” Pant says. “The same occurs in our human system — there are motor proteins that transport important cellular cargoes such as proteins, RNA and lipids from one part of the cell to another.”

Researchers around the world have identified mutations in KIF5A that lead to ALS, but important questions remain.

With the help of collaborators at Emory, Heidelberg, Germany, and the Albert Einstein College of Medicine in the Bronx, Pant set about answering this question: How does a defect in this specific motor protein cause disturbances in the body that can lead to ALS?

Using a fruit fly (Drosophila) model, the team found that when the mutant motor protein was expressed in flies, the flies became paralyzed. This mimics ALS in humans, who experience progressive muscle weakness and paralysis.

“Using single-molecule microscopy, we observed that ALS mutant motor protein is continuously active even in the absence of cargo. This leads to an abnormal accumulation of mutant motor protein in aggregates, which could cause the toxicity we observed in our model system,” Pant says.

The presence of mutant protein in KIF5A ALS patients was confirmed, with help from colleagues in Germany, by using a newly developed antibody. The findings have been validated by several independent research labs and potential therapies are being developed for clinical trials based on the study.  

Metabolic disturbances and juvenile ALS

Pant is also investigating a gene, SPTLC1, related to juvenile ALS, through research funded by the Live Like Lou Foundation and the ALS Association. Mutations in this gene were linked to a form of ALS in children in 2021.

“This gene, SPTLC1, is from the same lipid pathway that I worked on in my PhD program,” Pant says. “If you look at the history of the ALS patient, there is a continuous body weight loss. I think there is an early lipid metabolism involvement in ALS, irrespective of the nature of the disease — whether it is sporadic or genetic. With this genetic mutation of juvenile ALS, we are trying to understand these metabolic disturbances that ultimately lead to the disease.”

Perhaps the most famous case of juvenile ALS was seen in physicist and author Stephen Hawking, who was diagnosed when he was 21 and lived with the disease for 55 years — an extremely rare outcome.

In search of treatments

“In our lab, we are not discovering any new genes,” Pant says. “All the new ALS-associated genes are identified mainly by clinical geneticists worldwide who see the patients, send patient samples in for genomic sequencing and identify novel mutations. We get the mutation information and the associated pathological symptoms from these clinical centers. In the lab, we model these genetic mutations using animal models or stem cell cultures to better understand the molecular mechanisms that lead to ALS.”

In the ALS field, therapies are challenging. So far, no treatment can cure, minimize or even slow the disease progression. If researchers can develop treatments that block the impact of the genetic mutations, says Pant, they can provide therapeutic hope for patients. 

Without collaboration, the progress made so far would not have been possible.

“All this research requires funding. At Emory, the labs working on ALS have secured funding from many different organizations and sources, and we have a good collaborative team,” Pant says. “The environment here allows you to do multidisciplinary research — cell cultures, longitudinal animal models, organoid systems, up to human clinical trials. There is a rich pool of talent in-house, which allows you to get things done on campus in a timely manner.”

Partnerships also allow for broad collaboration. “For example, the CDC, which is right next to us, is developing a large biobank of ALS patients that will be a very good resource.”

Helping ALS patients and families

While Pant is primarily a researcher, he’s also been a conduit for families in search of help. 

“I’ve met some of the patients, and it provides more motivation to find a solution for them and their families,” he says. “It’s nice to tell them about the research we are doing.”

In one instance, he was contacted by a family in Kentucky whose daughter has juvenile ALS. Their physician told them a genetic mutation could be responsible, but they didn’t know the next steps to take. 

“I linked them to the ALS Association and experts that are following up with the family,” he says. “Also, the Live Like Lou Foundation can sometimes help with ALS family grants. So, I try my best to help. I do get emotional when I think about these patients and their families.”