Feinberg
Northwestern Medicine | Northwestern University | Faculty Profiles

News Center

  • Categories
    • Campus News
    • Disease Discoveries
    • Clinical Breakthroughs
    • Education News
    • Scientific Advances
  • Press Releases
  • Media Coverage
  • Podcasts
  • Editor’s Picks
    • COVID-19
    • Cardiology
    • Cancer
    • Neurology and Neuroscience
    • Aging and Longevity
    • Artificial Intelligence in Medicine
  • News Archives
  • About Us
    • Media Contact
    • Share Your News
    • News Feeds
    • Social Media
    • Contact Us
Menu
  • Categories
    • Campus News
    • Disease Discoveries
    • Clinical Breakthroughs
    • Education News
    • Scientific Advances
  • Press Releases
  • Media Coverage
  • Podcasts
  • Editor’s Picks
    • COVID-19
    • Cardiology
    • Cancer
    • Neurology and Neuroscience
    • Aging and Longevity
    • Artificial Intelligence in Medicine
  • News Archives
  • About Us
    • Media Contact
    • Share Your News
    • News Feeds
    • Social Media
    • Contact Us
Home » Uncovering the Cellular Mechanisms Behind Genetic Mutations in ALS
Disease Discoveries

Uncovering the Cellular Mechanisms Behind Genetic Mutations in ALS

By Melissa RohmanFeb 13, 2020
Share
Facebook Twitter Email
The nucleus (blue) of an ALS motor neuron demonstrating nonsense-mediated decay activation (red) within nuclear membrane invaginations (green) made possible with expansion microscopy. Provided by Elizabeth Daley.

Northwestern Medicine scientists have discovered that a genetic mutation found in amyotrophic lateral sclerosis (ALS) patients disrupts the localization of proteins involved in RNA and protein metabolism and leads to the dysfunction and eventual degeneration of motor neurons, according to a study published in Neuron.

The findings, which shed light on the mechanisms and consequences of a defect in the gene, known as C9orf72, may aid the development of novel therapeutic interventions for patients with the neurodegenerative disease, which currently has no cure.

Evangelos Kiskinis, PhD, assistant professor in the Ken and Ruth Davee Department of Neurology and of Physiology, was senior author of the study published in Neuron.

“Our study shows very interesting ways of how a neuron tries to defend itself from cellular stress inferred by the C9orf72 mutation. For instance, we found that motor neurons form nuclear invaginations that accumulate the necessary machinery required to adjust the level of protein and RNA metabolism,” said Juan Alberto Ortega, PhD, a postdoctoral fellow in the Kiskinis laboratory at the Les Turner ALS Center and co-first author of the study.

Previous work has found that this genetic mutation impairs the exchange of molecules between the nucleus and the cytosol, a process known as nucleocytoplasmic trafficking in which proteins and ribonucleic acid (RNA) move across the nuclear envelope of a cell.

“What we wanted to identify, however, was what are the proteins that are redistributed as a result of this trafficking defect,” said Evangelos Kiskinis, PhD, assistant professor in the Ken and Ruth Davee Department of Neurology and senior author of the study.

For the study, the scientists used subcellular fractionation — a method which involves the biochemical separation of the nucleus from the rest of the cell — and mass spectrometry to conduct subcellular proteomic screening in a cellular model of ALS.

From this analysis, the scientists found that there is an imbalance of the nuclear and cytoplasmic proteome in the ALS cells, and this imbalance targets proteins involved in RNA and protein metabolism. Additionally — and unexpectedly — the team also found that the eRF1 protein, which is normally found in the cytosol of a cell, accumulates within nuclear invaginations in neurons and plays a major role in the pathophysiology of the disease.

Then, using in vitro and in vivo models of the protein, the scientists found that eRF1 shifts the balance between protein translation and RNA degradation through a quality control pathway called nonsense-mediated decay.

“Our specific protein of interest, eRF1, mediates the balance between translation and RNA degradation by nonsense mediated decay,” said Kiskinis, who is also a professor in the Division of Neuromuscular Disease and of Physiology. “What we found was that this protein accumulates within nuclear invaginations, and triggers a reduction in protein translation and an increase in the degradation of RNA molecules including the mutant C9orf72 transcript itself. To be able to visualize eRF1 within these invaginations we had to use expansion microscopy.”

According to Kiskinis, these findings shed light on a cell-intrinsic pathway that degrades the mutant RNA; finding a way to trigger that pathway could be therapeutically relevant.

“This study is exciting because, based on an unbiased approach, our findings pointed to a specific RNA degradation pathway, which may be a key underlying component of disease,” said Elizabeth Daley, a fifth year graduate student in the Northwestern University Interdepartmental Neuroscience Program (NUIN) and co-first author of the study.

Seed funding for the laboratory’s work on ALS was provided by the Les Turner ALS Foundation, while  support by the New York Stem Cell Foundation, which recently awarded Kiskinis a New York Stem Cell Foundation – Robertson Investigator Award, will enable the continuous investigation of degenerative mechanisms in ALS.

This work was supported by the National Institutes of Health National Institute on Neurological Disorders (NINDS) and Stroke and National Institute on Aging grant R01NS104219, NIH and NINDS grants R21NS111248 and R21NS107761.

Faculty Neurology and Neuroscience Physiology Students
Share. Facebook Twitter Email

Related Posts

Sex-Specific Mechanisms for Major Depressive Disorder Identified in Response to Dysregulated Stress Hormones

Mar 23, 2023

Humans are Not Just Big Mice: Identifying Science’s Muscle-Scaling Problem

Mar 20, 2023

AOA Honors New Members

Mar 20, 2023

Comments are closed.

Latest News

Sex-Specific Mechanisms for Major Depressive Disorder Identified in Response to Dysregulated Stress Hormones

Mar 23, 2023

Pre-Surgery Immunotherapy May Increase Survival in Advanced Melanoma

Mar 23, 2023

Hormone Therapy Plus Current Treatments Improves Survival in Prostate Cancer

Mar 22, 2023

How ChatGPT Has, and Will Continue to, Transform Scientific Research

Mar 21, 2023

New Directions for HIV Treatment

Mar 21, 2023
  • News Center Home
  • Categories
  • Press Release
  • Media Coverage
  • Editor’s Picks
  • News Archives
  • About Us
Flickr Photos
20230317_NM651
20230317_NM610
20230317_NM569
20230317_NM537
20230317_NM331
20230317_NM323
20230317_NM316
20230317_NM336
20230317_NM626
20230317_NM662
20230317_NM655
20230317_NM642

Northwestern University logo

Northwestern University Feinberg School of Medicine

RSS Facebook Twitter LinkedIn Flickr YouTube Instagram
Copyright © 2023 Northwestern University
  • Contact Northwestern University
  • Disclaimer
  • Campus Emergency Information
  • Policy Statements

Type above and press Enter to search. Press Esc to cancel.