Fruit flies reveal mechanism behind ALS-like disease
Neurons are shown in green. A normal neuron is on the left and p150glued mutant neuron is on the right. The red cargo accumulates in the mutant but not in the normal neuron. Areas with the highest cargo accumulation are yellow at the tip of the neuron.
(Medical Xpress) -- Studying how nerve cells send and receive messages, Johns Hopkins scientists have discovered new ways that genetic mutations can disrupt functions in neurons and lead to neurodegenerative disease, including amyotrophic lateral sclerosis (ALS).
In a report published April 26 in Neuron, the research team says it has discovered that a mutation responsible for a rare, hereditary motor neuron disease called hereditary motor neuropathy 7B (HMN7B) disrupts the link between molecular motors and the nerve cell tip where they reside. This mutation results in the production of a faulty protein that prevents material from being transported from the cells edge, which is located at the muscle and extends back toward its body in the central nervous system. In pinpointing how and where this cargo transport is disrupted, the scientists are now closer to understanding mechanisms underlying this condition and ALS.
An important question we need to answer is how defects in proteins that normally perform important cellular functions for neurons lead to disease, says Alex Kolodkin, Ph.D., a Howard Hughes Medical Institute Investigator and professor of neuroscience at the Johns Hopkins University School of Medicine. A major issue in understanding neurodegenerative diseases is determining how certain proteins that are expressed in all types of neurons, or even in all cells in the body, can lead to devastating effects in one, or a few, subsets of neurons. Kolodkin notes that many neurodegenerative diseases involve proteins that serve general functions required in nearly every type of cell in the body, including the transport of material between different parts of a cell, yet certain alterations in these proteins can result in specific neurological disorders.
One particular protein, p150glued, is known to play a role in at least two of these disorders, HMN7B, which is similar to ALS, and Perry syndrome, which leads to symptoms similar to Parkinsons disease. p150glued is part of a larger complex of proteins that forms a molecular motor capable of transporting various molecules and other cargo from the nerve end toward the cell body. To better understand how mutations in p150glued lead to HMN7B and Perry syndrome, the researchers turned to fruit flies, which are easy to genetically manipulate and where the same protein has been well studied.
They engineered the fruit fly p150glued protein to contain the same mutations as those implicated in the two diseases and used microscopy techniques that enable them to follow in live cells the movement of fluorescently tagged cargo along motor neurons.
They found, surprisingly, that the movement of cargo along the length of the cell was normal. However, at the far end of the cell, they found that the HMN7B-associated mutation caused an unusually large accumulation of cargo. This was an unexpected finding, says Thomas Lloyd, M.D., Ph.D., an assistant professor in neurology and neuroscience at the Johns Hopkins School of Medicine. We need to better understand how this is causing disease.
Using flies engineered to contain mutations in other motor proteins, and again watching cargo transport in live cells, the team found that p150glued works in concert with another motor to control cargo transport. Their results suggest that when p150glued is compromised, this control is lost and cargo accumulates at the nerve end, leading to disease.
Its still unclear how these two different mutations in different regions of the same protein cause very distinct neurodegenerative diseases, Lloyd says. Encouraged by their results, the team plans to continue using fruit flies to unravel the molecular mechanisms underlying these diseases.
In addition to Lloyd and Kolodkin, other investigators participating in this research include James Machamer, Kathleen OHara, Ji Han Kim, Sarah Collins, Brooke Sahin, and Yunpeng Yang, Johns Hopkins; Man Y. Wong and Edwin Levitan, University of Pittsburgh; and Wendy Imlach and Brian McCabe, Columbia University Medical Center.
Journal reference: Neuron
Provided by Johns Hopkins University
- Brain disorder suggests common mechanism may underlie many neurodegenerative diseases Jan 11, 2009 | not rated yet | 0
- Scientists reveal new survival mechanism for neurons Aug 30, 2011 | not rated yet | 0
- Alzheimer's molecule is a smart speed bump on the nerve-cell transport highway Jan 17, 2008 | not rated yet | 0
- Researchers 'switch off' neurodegeneration in mice May 08, 2012 | not rated yet | 0
- Mutation may cause inherited neuropathy Dec 26, 2007 | not rated yet | 0
- Motion perception revisited: High Phi effect challenges established motion perception assumptions Apr 23, 2013 | 3 / 5 (2) | 2
- Anything you can do I can do better: Neuromolecular foundations of the superiority illusion (Update) Apr 02, 2013 | 4.5 / 5 (11) | 5
- The visual system as economist: Neural resource allocation in visual adaptation Mar 30, 2013 | 5 / 5 (2) | 9
- Separate lives: Neuronal and organismal lifespans decoupled Mar 27, 2013 | 4.9 / 5 (8) | 0
- Sizing things up: The evolutionary neurobiology of scale invariance Feb 28, 2013 | 4.8 / 5 (10) | 14
Why is zone 1 in liver more prone to ischemic injury?
May 23, 2013 Hi, Is it because around central vein, there is only deoxygenated blood from the vein where as in the periphery there is hepatic artery. Also why...
How can there be villous adenoma in colon, if there are no villi there
May 22, 2013 As title suggest. Thanks :smile:
How can there be a term called "intestinal metaplasia" of stomach
May 21, 2013 Hello everyone, Ok Stomach's normal epithelium is simple columnar, now in intestinal type of adenocarcinoma of stomach it undergoes "intestinal...
Pressure-volume curve: Elastic Recoil Pressure don't make sense
May 18, 2013 From pressure-volume curve of the lung and chest wall (attached photo), I don't understand why would the elastic recoil pressure of the lung is...
If you became brain-dead, would you want them to pull the plug?
May 17, 2013 I'd want the rest of me to stay alive. Sure it's a lousy way to live but it beats being all-the-way dead. Maybe if I make it 20 years they'll...
MRI bill question
May 15, 2013 Dear PFers, The hospital gave us a $12k bill for one MRI (head with contrast). The people I talked to at the hospital tell me that they do not...
- More from Physics Forums - Medical Sciences
More news stories
New research presented today shows that formation of new neurons in the hippocampus - a brain region known for its importance in learning and remembering - could cause forgetting of old memories by causing a reorganization ...
Neuroscience 6 hours ago | 5 / 5 (2) | 0
How can healthy people who hear voices help schizophrenics? Finding the answer for this is at the centre of research conducted at the University of Bergen.
Neuroscience 6 hours ago | 4 / 5 (2) | 2
One of the major frontiers of modern science is a comprehensive understanding of the human brain and its functions to guide the development of new technologies in information and communication. In a major announcement for ...
Neuroscience 7 hours ago | 1 / 5 (1) | 0
(Medical Xpress)—Regulating the distribution of power in neurons is done by a system that makes the national electric grid look simple by comparison. Each neuron has several thousand mitochondria confined ...
Neuroscience 22 hours ago | 4.9 / 5 (9) | 0 |
(Medical Xpress)—The human brain is able to identify individuals' voices by comparing them against an internal 'average voice' prototype, according to neuroscientists.
Neuroscience May 23, 2013 | 3 / 5 (2) | 3 |
Talking on a hands-free device while behind the wheel can lead to a sharp increase in errors that could imperil other drivers on the road, according to new research from the University of Alberta.
46 minutes ago | not rated yet | 0
(AP)—Government health officials are investigating several health problems reported with potentially contaminated medications made by a Tennessee specialty pharmacy.
1 hour ago | not rated yet | 0
Two mutations central to the development of infantile myofibromatosis (IM)—a disorder characterized by multiple tumors involving the skin, bone, and soft tissue—may provide new therapeutic targets, according to researchers ...
1 hour ago | not rated yet | 0 |
(Medical Xpress)—A new study by researchers in the US has shown that an ancient virus can be modified to help in the fight against the simian immunodeficiency virus SIV, which is the equivalent in monkeys ...
6 hours ago | 5 / 5 (3) | 0 |
Women at a particular stage in their monthly menstrual cycle may be more vulnerable to some of the psychological side-effects associated with stressful experiences, according to a study from UCL.
3 hours ago | 5 / 5 (1) | 0 |
Biological processes are generally based on events at the molecular and cellular level. To understand what happens in the course of infections, diseases or normal bodily functions, scientists would need to ...
4 hours ago | 5 / 5 (2) | 0 |