Published May 22, 2013
Neuroscientists at the University at Buffalo’s Hunter
James Kelly Research Institute (HJKRI) and European colleagues
have provided proof of principle for how a genetic mutation leads
to some neuropathies.
The international team also used a research drug to successfully
alleviate the protein synthesis misstep, thereby improving myelin.
Myelin is the fatty material that wraps the axons of neurons and
allows them to signal effectively.
As a result, a potential new treatment strategy may be on the horizon for patients with a host of neurological disorders that result from misfolded proteins.
The researchers studied a genetic mutation that causes neuropathy in Charcot-Marie-Tooth (CMT) disease, but their findings may also be relevant to Alzheimer’s disease, Parkinson’s disease, multiple sclerosis, Type 1 diabetes, cancer and mad cow disease.
Results of the study, “Resetting Translational Homeostasis Restores
Myelination in Charcot-Marie-Tooth Disease Type 1B Mice,”
have been published in The
Journal of Experimental Medicine. Lawrence Wrabetz, MD, director of the
institute and professor of neurology
and biochemistry, is senior author.
The study centers on the synthesis of misfolded proteins in
Schwann cells, which make myelin in nerves.
When cells recognize that the misfolded proteins are being synthesized, they respond by severely reducing protein production, Wrabetz explains.
The process goes awry when the cells then re-commence protein synthesis and a protein called Gadd34 gets involved.
Once Gadd34 is turned back on, it activates synthesis of proteins at too high a level, causing more problems in myelination, the researchers discovered.
“We have provided proof of principle that Gadd34 causes a problem with translational homeostasis and that’s what causes some neuropathies,” says Wrabetz.
This crucial process regulates new protein production so that cells maintain a precise balance between lipids and proteins.
The researchers also are exploring a possible solution to the protein synthesis problem.
They have succeeded in improving myelin using salubrinal, a small-molecule research drug, to reduce Gadd34 in both cultures and a transgenic mouse model of CMT neuropathies.
“We’ve shown that if we just reduce Gadd34, we
actually get better myelination. So, leaving protein synthesis
turned partially off is better than turning it back on
completely,” says Wrabetz.
Wrabetz and his colleagues are now working to develop derivatives of salubrinal that are appropriate for human use.
“If we can demonstrate that a new version of this molecule is safe and effective, then it could be part of a new therapeutic strategy for CMT and possibly other misfolded protein diseases,” he says.
CMT is complex, caused by mutations in more than 40 different
genes. Like some other neurodegenerative diseases, a subset of
these CMT neuropathies is associated with misfolded proteins,
“When there are so many different genes involved and so many different mechanisms, you have to find a unifying mechanism,” he notes. Misfolded proteins and Gadd34 turning on protein synthesis at too high a level could be just that.
“The hope is that this proof of principle applies to more than just CMT and may lead to improved treatments for Alzheimer’s disease, Parkinson’s disease, Type 1 diabetes and the other diseases caused by misfolded proteins,” he says.
While the researchers have focused on CMT, which is among the most common hereditary neurological disorders, their work is enriching the understanding of myelin disorders in general.
“What we learn in one disease, such as CMT, may inform how we think about toxins for others, such as Krabbe Leukodystrophy,” Wrabetz says. “We’d like to build a foundation and answer basic questions about where and when toxicity in diseases begins.”
Previously, Wrabetz has shown in experiments with transgenic mice that mutations in the P0 gene cause myelin to break down, which in turn, causes degeneration of peripheral nerves and wasting of muscles.
Finding more answers could benefit many. Diseases causing neuropathy often significantly diminish quality of life but not longevity, taking a major toll on patients, families and society, the researchers note.
The study also involved co-author M. Laura Feltri, MD, professor of neurology and biochemistry and a HJKRI researcher.
Other collaborators include lead author Maurizio
D’Antonio, PhD, and colleagues from the San Raffaele
Scientific Institute in Italy, where Wrabetz and Feltri did most of
this research. Another researcher from the National Institute for
Health Research Cambridge Biomedical Research Centre in England
Funding was provided by the National Institutes of Health, the European Community and the Italian Ministry of Health.
The HJKRI, founded in 2008 in partnership with UB, is located in UB’s New York State Center of Excellence in Bioinformatics and Life Sciences.
As the research arm of the Hunter’s Hope Foundation, the institute supports studies and seeks treatments for myelin-related diseases, such as Krabbe disease and other leukodystrophies.
It was established by Jim Kelly, Buffalo Bills Hall of Fame quarterback, and his wife, Jill, after their late son, Hunter, was diagnosed with Krabbe, an inherited, fatal disorder of the nervous system.