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 » Protein Quality Control Falters in Neurodegenerative Disease
Disease Discoveries

Protein Quality Control Falters in Neurodegenerative Disease

By Will DossMay 31, 2019
Share
Facebook Twitter Email
Robert Kalb, MD, director of the Les Turner ALS Center at Northwestern Medicine, chief of Neuromuscular Disease in the Ken and Ruth Davee Department of Neurology and the Les Turner Professor, was a co-author of the study published in Nature Neuroscience.

Northwestern scientists have discovered how certain genetic mutations can weaken protein “quality control,” identifying a pathway that may contribute to several neurodegenerative diseases.

The study, published in Nature Neuroscience, identified Lethal (3) malignant brain tumor-like protein 1 (L3MBTL1) as a major weak point: Higher-than-normal levels of L3MBTL1 were associated with impaired protein homeostasis in mice with amyotrophic lateral sclerosis (ALS). Nullifying L3MBTL1 using therapeutics could represent a new treatment strategy for these diseases, the authors said, although additional investigation is required.

“This work continues to strengthen the case that protein quality control is a fundamental problem in neurodegenerative disease,” said Robert Kalb, MD, director of the Les Turner ALS Center at Northwestern Medicine, chief of Neuromuscular Disease in the Ken and Ruth Davee Department of Neurology and the Les Turner Professor, and co-author of the study. “Deeper exploration of the ways cells handle damaged and misfolded proteins will reveal targets for therapeutic intervention. We are still early in this journey.”

Jelena Mojsilovic-Petrovic, MD, PhD, research assistant professor of Neurology in the Division of Neuromuscular Disease, was also a co-author of the study.

Protein homeostasis — the complex processes that regulate the amount of and stability of proteins — is vital for cellular fitness. Most organisms have developed sophisticated mechanisms to deal with misfolded proteins. This includes engagement of molecular chaperones (which can re-fold misfolded proteins) or protein degradation either through the ubiquitin-proteasomal pathway or the lysosomal autophagy pathway.

Many neurodegenerative diseases are characterized by accumulation of toxic proteins, pitting these systems in conflict with one another. Previous studies have found disposing of misfolded proteins through autophagy requires activation of p53, a common tumor-suppressing pathway, though the exact regulatory mechanisms are poorly understood.

Using both worm and mouse models, Kalb and colleagues knocked out expression of L3MBTL1, finding that afterwards, the mice experienced accelerated protein degradation through the p53 pathway. They also discovered another influence on this pathway, SET domain-containing protein 8 (SETD8), that was involved with aberrant protein disposal in a similar but distinct role.

When levels of misfolded proteins were reduced, mouse models experienced fewer motor system symptoms, such as poor locomotion, and p53 played a central role in both pathways.

“The data collectively suggest that p53 is a master regulatory switch for protein quality control,” Kalb said. “The new findings implicating p53 in the protein quality control network are of outstanding importance, because now we can leverage what we know about p53 in the cancer world and apply it in the neurodegeneration world.”

Because both proteins were present at high levels in the central nervous systems of mice with ALS, this may indicate there is some mechanism in the disease that upregulates the proteins, making it easier for toxic proteins to proliferate throughout the brain.

If scientists could discover how ALS upregulates these proteins, they would have a new target for therapeutic intervention that could boost ALS patients’ ability to clear out these toxic proteins.

The study was supported by grants from the National Institutes of Health grants NS074324, NS089616, NS110098, NS096746 and NS093439, the Packard Center for ALS Research at Johns Hopkins, the Muscular Dystrophy Association, the ALS Association and the Maryland Stem Cell Research Fund and the Les Turner ALS Center.

Genetics Neurology and Neuroscience Research
Share. Facebook Twitter Email

Related Posts

Investigating Protein’s Role in Hearing Loss

Mar 27, 2023

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

Comments are closed.

Latest News

Weintraub Appointed to Illinois Supreme Court Commission on Elder Law

Mar 28, 2023

Investigating Protein’s Role in Hearing Loss

Mar 27, 2023

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
  • 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.