04-27-2013, 08:13 AM
Many neurological diseases are caused by misfolded proteins in the brain and along the nervous system. These include Charcot-Marie-Tooth disease, Parkinson’s disease, multiple sclerosis, and Alzheimer’s disease. The misfolfded proteins seem to cause damage to the nervous system and prevent proper functioning of the brain and other parts of the nervous system. These diseases are not reversible, and there are no available treatments to help properly fold the proteins after disease has begun.
Charcot-Marie-Tooth (CMT) is a group of diseases that affect the peripheral nervous system in which the myelin sheaths surrounding the nerve cells are not properly formed. Myelin is a fatty material that is produced by a type of cell called Schwann cells. The myelin acts to insulate the nerve cells, allowing electrical impulses to quickly and easily be conducted throughout the body. Breakdown of the myelin sheath due to CMT results in a decreased ability of the nerve to transmit signals, and leads to degeneration of the nerve. The muscle cell activated by the nerve becomes weakened and atrophied due to lack of use, and this is a hallmark of CMT. CMT is one of the most common inherited neurological disorders, affecting about one in every twenty five hundred people in the United States. CMT is a progressive neuropathy, which means that the condition continues to worsen over time. Although CMT is not fatal in and of itself, it can cause severe effects, limiting mobility and decreasing quality of life.
A common mutation associated with certain types ofCMT is in a protein called P0. P0 seems to act as a molecular glue that holds the myelin around the neuron. If the protein is mutated, then the myelin is not properly attached to myelin. Mutations in P0 have been linked to neuron degeneration and muscle wasting in mice.
Researchers at the University of Buffalo found that when the cell detects defective or misfolded P0 being produced, production of protein is shut off. After the cell has corrected the problem, a protein called Gadd34 causes the cell to resume production of P0. Unfortunately, the Gadd34 causes very high levels of P0 and myelin to be produced, which actually causes more dysfunction in the cell. The excess production of P0 prevents adequate attachment of myelin to the outside of the nerve cell. The researchers found that simply reducing the level of Gadd34 present in the Schwann cells results in increased myelination of the nerve cell. The researchers were able to improve myelin production for nerve cells in both tissue culture and transgenic mouse models.
It will take time and research before this information can be translated into human studies. Researchers will first need to determine if Gadd34 has the same effect on myelin production in human Schwann cells as it does in mouse cells. Because the drug used in tissue culture and in the mouse trials is not approved for human use, the researchers will then need to find or develop a safe molecule that can be given to human volunteers to reduce the level of Gadd34 in the Schwann cells. They will also need to determine the best route of introduction of this molecule. Then, the researchers will need to determine how effectively the rebuilding of the myelin sheath around nerve cells can help restore nerve function. After nerve function is restored, patients would still require physical therapy to help restore muscle function. All of this will take many years to complete, but the prospect of any potential therapy against CMT or other similar neurological diseases is encouraging.
Neuropathies such as CMT are difficult to study, because they may be due to mutations in dozens of genes. The different variations of CMT are also most likely caused by mutations in different genes, and are inherited in different patterns. CMT can be inherited as either a sex-linked disorder or as an autosomal disorder, and can be controlled by either recessive or dominant genes. This diversity of different genetic causes of CMT also means that any potential treatments would need to address all of the potential mutations. One reason Gadd34 is so exciting to researchers is that it could potentially address multiple proteins that are being made incorrectly. Inhibition of Gadd34 could therefore be used to treat multiple types of CMT, as well as other neurothapies.
References:
http://www.sciencedaily.com/releases/201...135037.htm
http://www.ninds.nih.gov/disorders/charc..._tooth.htm
Charcot-Marie-Tooth (CMT) is a group of diseases that affect the peripheral nervous system in which the myelin sheaths surrounding the nerve cells are not properly formed. Myelin is a fatty material that is produced by a type of cell called Schwann cells. The myelin acts to insulate the nerve cells, allowing electrical impulses to quickly and easily be conducted throughout the body. Breakdown of the myelin sheath due to CMT results in a decreased ability of the nerve to transmit signals, and leads to degeneration of the nerve. The muscle cell activated by the nerve becomes weakened and atrophied due to lack of use, and this is a hallmark of CMT. CMT is one of the most common inherited neurological disorders, affecting about one in every twenty five hundred people in the United States. CMT is a progressive neuropathy, which means that the condition continues to worsen over time. Although CMT is not fatal in and of itself, it can cause severe effects, limiting mobility and decreasing quality of life.
A common mutation associated with certain types ofCMT is in a protein called P0. P0 seems to act as a molecular glue that holds the myelin around the neuron. If the protein is mutated, then the myelin is not properly attached to myelin. Mutations in P0 have been linked to neuron degeneration and muscle wasting in mice.
Researchers at the University of Buffalo found that when the cell detects defective or misfolded P0 being produced, production of protein is shut off. After the cell has corrected the problem, a protein called Gadd34 causes the cell to resume production of P0. Unfortunately, the Gadd34 causes very high levels of P0 and myelin to be produced, which actually causes more dysfunction in the cell. The excess production of P0 prevents adequate attachment of myelin to the outside of the nerve cell. The researchers found that simply reducing the level of Gadd34 present in the Schwann cells results in increased myelination of the nerve cell. The researchers were able to improve myelin production for nerve cells in both tissue culture and transgenic mouse models.
It will take time and research before this information can be translated into human studies. Researchers will first need to determine if Gadd34 has the same effect on myelin production in human Schwann cells as it does in mouse cells. Because the drug used in tissue culture and in the mouse trials is not approved for human use, the researchers will then need to find or develop a safe molecule that can be given to human volunteers to reduce the level of Gadd34 in the Schwann cells. They will also need to determine the best route of introduction of this molecule. Then, the researchers will need to determine how effectively the rebuilding of the myelin sheath around nerve cells can help restore nerve function. After nerve function is restored, patients would still require physical therapy to help restore muscle function. All of this will take many years to complete, but the prospect of any potential therapy against CMT or other similar neurological diseases is encouraging.
Neuropathies such as CMT are difficult to study, because they may be due to mutations in dozens of genes. The different variations of CMT are also most likely caused by mutations in different genes, and are inherited in different patterns. CMT can be inherited as either a sex-linked disorder or as an autosomal disorder, and can be controlled by either recessive or dominant genes. This diversity of different genetic causes of CMT also means that any potential treatments would need to address all of the potential mutations. One reason Gadd34 is so exciting to researchers is that it could potentially address multiple proteins that are being made incorrectly. Inhibition of Gadd34 could therefore be used to treat multiple types of CMT, as well as other neurothapies.
References:
http://www.sciencedaily.com/releases/201...135037.htm
http://www.ninds.nih.gov/disorders/charc..._tooth.htm
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