Corporate Banner
Satellite Banner
Proteomics
Scientific Community
 
Become a Member | Sign in
Home>News>This Article
  News
Return

Improper Protein Digestion in Neurons Identified as a Cause of Familial Parkinson’s

Published: Friday, March 08, 2013
Last Updated: Friday, March 08, 2013
Bookmark and Share
Researchers at CUMC and others have discovered how the most common genetic mutations in familial Parkinson’s disease damage brain cells.

The mutations block an intracellular system that normally prevents a protein called alpha-synuclein from reaching toxic levels in dopamine-producing neurons. The findings suggest that interventions aimed at enhancing this digestive system, or preventing its disruption, may prove valuable in the prevention or treatment of Parkinson’s. The study was published March 3 in the online edition of the journal Nature Neuroscience.

Parkinson’s disease is characterized by the formation of Lewy bodies (which are largely composed of alpha-synuclein) in dopamine neurons. In 1997, scientists discovered that a mutation in alpha-synuclein can lead to Lewy body formation. “But alpha-synuclein mutations occur in only a tiny percentage of Parkinson’s patients,” said co-lead author David L. Sulzer, PhD, professor of neurology, pharmacology, and psychiatry at CUMC. “This meant that there must be something else that interfered with alpha-synuclein in people with Parkinson’s.”

Dr. Sulzer and his colleagues suspected that a gene called leucine-rich repeat kinase-2 (LRRK2) might be involved. LRRK2 mutations are the most common mutations to have been linked to Parkinson’s. The current study aimed to determine how these mutations might lead to the accumulation of alpha-synuclein.

“We found that abnormal forms of LRRK2 protein disrupt a critical protein-degradation process in cells called chaperone-mediated autophagy,” said Dr. Sulzer. “One of the proteins affected by this disruption is alpha-synuclein. As this protein starts to accumulate, it becomes toxic to neurons.” Delving deeper, the researchers found that LRRK2 mutations interfere with LAMP-2A, a lysosome membrane receptor that plays a key role in lysosome function.

(Chaperone-mediated autophagy, or CMA, is responsible for transporting old or damaged proteins from the cell body to the lysosomes, where they are digested into amino acids and then recycled. In 2004, Dr. Sulzer and the current paper’s other co-lead author, Ana Maria Cuervo, MD, PhD, professor of developmental & molecular biology, of anatomy & structural biology, and of medicine at Albert Einstein College of Medicine of Yeshiva University, showed that alpha-synuclein is degraded by the CMA pathway.)

“Now that we know this step that may be causing the disease in many patients, we can begin to develop drug treatments or genetic treatments that can enhance the digestion of these disease-triggering proteins, alpha-synuclein and LRRK2, or that remove alpha-synuclein,” said Dr. Sulzer.

While LRRK2 mutations are the most common genetic cause of Parkinson’s, it is too early to tell whether these findings, and therapies that might stem from them, would apply to patients with non-familial Parkinson’s, the more common form of the disease. “Right now, all we can say is that it looks as though we’ve found a fundamental pathway that causes the buildup of alpha-synuclein in people with LRRK2 mutations and links these mutations to a common cause of the disease. We suspect that this pathway may be involved in many other Parkinson’s patients,” said Dr. Sulzer.

The study involved mouse neurons in tissue culture from four different animal models, neurons from the brains of patients with Parkinson’s with LRRK2 mutations, and neurons derived from the skin cells of Parkinson’s patients via induced pluripotent stem (iPS) cell technology. All the lines of research confirmed the researchers’ discovery.

The paper is titled “Interplay of LRRK2 with chaperone-mediated autophagy.” The other contributors are Samantha J. Orenstein (Einstein), Sheng-Han Kuo (CUMC), Inmaculada Tasset (Einstein), Esperanza Arias (Einstein), Hiroshi Koga (Einstein), Irene Fernandez-Carasa (University of Barcelona, Barcelona Spain), Etty Cortes (CUMC), Lawrence S. Honig (CUMC), William Dauer (University of Michigan, Ann Arbor, MI), Antonella Consiglio (University of Barcelona and University of Brescia, Brescia, Italy), and Angel Raya (Insitucio Catalana de Recerca I Estudies Avancas and Center for Networked Biomedical Research on Bioengineering, Biomaterials and Nanomedicine, Barcelona, Spain).

The collaboration of Sulzer and Cuervo was supported by a Udall Center of Excellence for Research in Parkinson’s Disease of the NIH National Institute of Neurological Disorders and Stroke. This work was further supported by grants from the JPB Foundation, the National Institute on Aging (AG031782 and AG08702); the Rainwater Foundation; the Beatrice and Roy Backus Foundation; the Parkinson’s Disease Foundation; Fondazione Guido Berlucchi; and Centers for Networked Biomedical Research, Ministry of Economy and Competitiveness and by a Hirschl/Weill-Caulier Career Scientist Award and a gift from Robert and Renee Belfer.

The authors declare no financial or other conflicts of interest.


Further Information
Access to this exclusive content is for Technology Networks Premium members only.

Join Technology Networks Premium for free access to:

  • Exclusive articles
  • Presentations from international conferences
  • Over 2,500+ scientific posters on ePosters
  • More than 3,800+ scientific videos on LabTube
  • 35 community eNewsletters


Sign In



Forgotten your details? Click Here
If you are not a member you can join here

*Please note: By logging into TechnologyNetworks.com you agree to accept the use of cookies. To find out more about the cookies we use and how to delete them, see our privacy policy.

Related Content

Long-term Memories Are Maintained by Prion-like Proteins
Research from Eric Kandel’s lab at Columbia University Medical Center has uncovered evidence of a system in the brain that persistently maintains memories for long periods of time.
Friday, July 03, 2015
Study Shows Where Alzheimer’s Starts and How It Spreads
The findings could improve early detection of the disease, when drugs may be most effective.
Tuesday, December 24, 2013
Global Study Discovers Flurry of New Alzheimer’s Genes
An international study has uncovered 11 new genes that increase the chance of developing Alzheimer’s disease and provide new clues to ways of fighting it.
Wednesday, October 30, 2013
Test Could Identify Which Prostate Cancers Require Treatment
3-gene biomarker gauges tumor’s aggressiveness.
Thursday, September 12, 2013
Scientific News
Cellular Contamination Pathway for Heavy Elements Identified
Berkeley Lab scientists find that an iron-binding protein can transport actinides into cells.
Lemon Juice and Human Norovirus
Citric acid may prevent the highly contagious norovirus from infecting humans, scientists discovered from the German Cancer Research Center.
Signature of Microbiomes Linked to Schizophrenia
Studying microbiomes in throat may help identify causes and treatments of brain disorder.
Structural Discoveries Could Aid in Better Drug Design
Scientists have uncovered the structural details of how some proteins interact to turn two different signals into a single integrated output.
Protein Found to Play a Key Role in Blocking Pathogen Survival
Calprotectin fends off microbial invaders by limiting access to iron, an important nutrient.
Study Identifies the Off Switch for Biofilm Formation
New discovery could help prevent the formation of infectious bacterial films on hospital equipment.
How DNA ‘Proofreader’ Proteins Pick and Edit Their Reading Material
Researchers from North Carolina State University and the University of North Carolina at Chapel Hill have discovered how two important proofreader proteins know where to look for errors during DNA replication and how they work together to signal the body’s repair mechanism.
Protein Found to Control Inflammatory Response
A new Northwestern Medicine study shows that a protein called POP1 prevents severe inflammation and, potentially, diseases caused by excessive inflammatory responses.
X-ray Laser Experiment Could Help in Designing Drugs for Brain Disorders
Scientists found that when two protein structures in the brain join up, they act as an amplifier for a slight increase in calcium concentration, triggering a gunshot-like release of neurotransmitters from one neuron to another.
Team Identifies Structure of Tumor-Suppressing Protein
An international group of researchers led by Carnegie Mellon University physicists Mathias Lösche and Frank Heinrich have established the structure of an important tumor suppressing protein, PTEN.
Scroll Up
Scroll Down
Skyscraper Banner

Skyscraper Banner
Go to LabTube
Go to eposters
 
Access to the latest scientific news
Exclusive articles
Upload and share your posters on ePosters
Latest presentations and webinars
View a library of 1,800+ scientific and medical posters
2,500+ scientific and medical posters
A library of 2,500+ scientific videos on LabTube
3,800+ scientific videos
Close
Premium CrownJOIN TECHNOLOGY NETWORKS PREMIUM FREE!