Mice point to a therapy for Charcot-Marie-Tooth disease
VIB researchers have developed a mouse model for Charcot-Marie-Tooth (CMT) neuropathy, a hereditary disease of the peripheral nervous system. They also found a potential therapy for this incurable disease. The treatment not only halted the damage to the nerves and the atrophy of the muscles, it even succeeded in reversing the symptoms.
The research was conducted under supervision of Wim Robberecht en Ludo Van Den Bosch from VIB-K.U.Leuven, in collaboration with the team of Vincent Timmerman at VIB-University of Antwerp. The study was published in Nature Medicine.
CMT: a collection of neuropathies
Charcot-Marie-Tooth (CMT) disease is the name for a collection of hereditary disorders and affects approximately one in 2,500 individuals, making it the most common inherited disorder of the peripheral nervous system. CMT is characterized by loss of muscle tissue due to denervation and by sensory abnormalities, both predominantly in feet and legs but also in the hands and arms in advanced stages of the disease. Persons with CMT can be affected moderately to quite severely. It is presently not possible to cure or prevent CMT, which affects both children and adults. Research into the molecular biological process leading to CMT is important, because it contributes to the development of good diagnosis and offers possible treatments.
Earlier work by VIB researchers showed that some CMT patients have mutations in HSPB1, a gene coding for the 27 kDa small heat shock protein B1, a protein that plays a role in many stress-related molecular processes in the body. Until now, it was unclear how mutations in HSPB1 could lead to degeneration of the nerve bundles and to muscular weakness.
Mouse model for CMT
The core of the study by Constantin van Outryve d'Ydewalle consists of the construction of a mouse model for CMT. The researchers expressed the mutated human HSPB1 gene in mouse neurons. The mouse model develops motor symptoms, muscle atrophy and weakness, foot deformities and steppage gait, all very similar to symptoms observed in affected individuals. Furthermore, the mice develop sensory problems that also occur in CMT patients. Pathological examination of the nerves of the CMT mice shows that the contact between the nerve endings and muscles is disturbed.
Axonal transport deficits
The CMT mice provide the unique possibility to isolate and culture affected nerve cells, making it possible to investigate what exactly goes wrong in the sick nerves. It was discovered that the transport of mitochondria (the cellular power plants) within the axons is severely disturbed in the neurons from symptomatic CMT mice, most likely because the tracks along which the mitochondria are transported (microtubules) are damaged. This could lead to a chronic lack of sufficient mitochondria and other transported cargoes at the nerve endings, causing the nerves to degenerate.
Possible treatment of CMT by HDAC6 inhibitors
These new insights also open possibilities for treatment, because the mitochondrial transport in nerve fibers is known to be affected by tubulin deacetylation, a posttranslational modification of the building blocks of microtubules catalyzed by histone deacetylase 6 (HDAC6). Inhibitors of HDAC6 do not only reverse the axonal transport deficits in vitro, treatment of the CMT mice with HDAC6 inhibitors also halts the damage to the nerves and even succeeds in reversing the symptoms, most likely by muscle reinnervation. The most specific therapeutic molecule used in this study (Tubastatin A) was made by Alan Kozikowski from the University of Illinois at Chicago (USA).
Mouse medicine is not the same as human medicine
There is still a long way to go before these drugs will become available for patients. Many experimental drugs even those that are successful in animal models fail during clinical trials due to problems with safety or the lack of therapeutic effectiveness. Still, the results of this study are important not only because of the CMT mouse model that replicates the symptoms of the human disease; it also opens perspectives for possible new treatments of an incurable disease.
Reduced axonal transport in neurons is also observed in other neurodegenerative or neurological diseases, opening the door for further investigations into the effects of this new therapeutic strategy in other diseases. Further scientific research is crucial to solve this issue.
Provided by VIB (the Flanders Institute for Biotechnology)
- Fruit fly steps in to fight human disease Jun 22, 2009 | not rated yet | 0
- Disease-causing mutation disrupts movement of cell's 'power house' Mar 23, 2010 | not rated yet | 0
- Mutation may cause inherited neuropathy Dec 26, 2007 | not rated yet | 0
- Hereditary Condition Causing Limb Weakness Traced to Gene for Rare Disorder Mar 12, 2010 | not rated yet | 0
- The downside of microtubule stability Jun 15, 2009 | 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
Learning curve of Electromagnetism?
3 hours ago I'm taking a first year physics course and have been having a little trouble with the basics of newtons laws and forces and whatnot, though nothing...
thin glass in liquid
3 hours ago I have one question about optics because I start interested in it. If an object is placed a distance p from a thin glass lens (index of refraction...
How many joules expended for a push up?
6 hours ago Just wondering if any of you can do the calculation that well approximates the amount of joules expended by a push up.
force to keep the folding doors
6 hours ago Hello, I would like to ask you to calculate the force F, which needed to keep the folding doors in this position. I would like to know what is the...
Confusion regarding direction of kinetic friction on inclined plane.
7 hours ago *please help! * The formula for kinetic friction acting on a sliding body is μkN When the body is sliding with constant velocity down an...
13 hours ago Alright, so in Pathfinder (like Dungeons and Dragons) there's a spell that allows you to lift/move stuff within 25 ft with 5 pounds of force. A...
- More from Physics Forums - Classical Physics
More news stories
(HealthDay)—Practitioners might consider discontinuing prophylactic antibiotics for patients with prosthetic implants undergoing dental procedures, and these patients should be encouraged to maintain appropriate ...
Dentistry May 14, 2013 | not rated yet | 0
A new report assessing the economic viability of services provided by practicing midlevel dental providers in the U.S. shows that they are expanding preventive dental care to people who need it most: children and those who ...
Dentistry May 14, 2013 | not rated yet | 0
(HealthDay)—Manifestation of dental erosion caused by illicit drug use or excessive soda consumption needs to be distinguished from dental caries, according to case studies published in the March/April ...
Dentistry May 13, 2013 | 5 / 5 (1) | 0
Are you wrecking your teeth without even knowing it? For instance, chewing on ice or opening stuff with your teeth may be convenient but using your teeth as tools can cause them to crack or chip.
Dentistry May 03, 2013 | 3 / 5 (1) | 1
Elderly or people with osteoporosis, smokers, diabetics or people who have had cancer are sometimes not eligible to receive dental implants as their bones are unable to correctly integrate the new prostheses which replace ...
Dentistry Apr 29, 2013 | not rated yet | 0
An increasing number of U.S. children are experiencing gastrointestinal issues that require interventions to resolve, according to research presented at Digestive Disease Week (DDW).
6 hours ago | not rated yet | 0 |
Big names in medicine are set to give an upbeat assessment of the war on AIDS on Tuesday, 30 years after French researchers identified the virus that causes the disease.
14 hours ago | 5 / 5 (1) | 0
For combat veterans suffering from post-traumatic stress disorder, 'fear circuitry' in the brain never rests
Chronic trauma can inflict lasting damage to brain regions associated with fear and anxiety. Previous imaging studies of people with post-traumatic stress disorder, or PTSD, have shown that these brain regions can over-or ...
15 hours ago | 5 / 5 (1) | 0 |
The latest makeover to a massive psychiatric tome honored by some, reviled by others and even called the "Bible" of mental disorders is being released Saturday with a host of new changes.
4 hours ago | not rated yet | 0
A new case of the deadly coronavirus has been detected in Saudi Arabia where 15 people have already died after contracting it, the health ministry announced on Saturday on its Internet website.
4 hours ago | not rated yet | 0
A ground-breaking advance in colonoscopy technology signals the future of colorectal care, according to research presented today at Digestive Disease Week(DDW). Additional research focuses on optimizing the minimal withdrawal ...
6 hours ago | 5 / 5 (1) | 0