Mutated protein contributes to Lou Gehrig's
A new finding by researchers at Hopkins's School of Medicine has elucidated a little-known molecular pathway in the development of amyotrophic lateral sclerosis (ALS), or Lou Gehrig's disease.
The study by Kevin Chen, Lee Martin and Frances Northington has discovered a malfunction mechanism that they believe can and does contribute to the development of ALS.
The mechanism involves overexpression of one protein in particular: inducible nitric oxide synthase (iNOS or NOS2). This protein seems to be upregulated, at least in part, by a mutated form of the gene encoding for the superoxide dismutase-1 (SOD1) enzyme.
Inducible nitric oxide synthase, as its name suggests, is an enzyme that synthesizes nitric oxide. Nitric oxide in the brain serves a variety of functions, one of which is its role as a freely diffusing neurotransmitter.
However, nitric oxide (NO) can also react with a form of oxygen called the superoxide anion (O2-) to form highly reactive and destructive products. Usually the superoxide anion is processed into a less harmful form by the SOD1 protein.
When SOD1 is not working properly, highly reactive products of nitric oxide and the superoxide anion can accumulate and cause extensive damage. These products, such as the peroxynitrite ion, damage cells by attacking key molecular building blocks like amino acids, lipids and nucleic acids.
"Motor neurons, which are uniquely vulnerable in ALS, are also unique in that they express . . . very, very low levels [of] iNOS normally, even without any ALS pathology," Martin said. "Furthermore, and quite interestingly, even before symptoms of ALS emerge at a macro, observable level, the level of iNOS expressed in some cells increases noticeably, most specifically in the motor neurons of the spinal cord and the brainstem."
Later on, however, the greatest upregulation of iNOS is not in these cells, but rather in some microglia and astrocytes. Microglia and astrocytes are two types of neuronal support cells. Usually, they help to protect neurons or deliver nutrients and neurotransmitter precursors to neurons.
The study by Kevin Chen, Lee Martin and Frances Northington has discovered a malfunction mechanism that they believe can and does contribute to the development of ALS.
The mechanism involves overexpression of one protein in particular: inducible nitric oxide synthase (iNOS or NOS2). This protein seems to be upregulated, at least in part, by a mutated form of the gene encoding for the superoxide dismutase-1 (SOD1) enzyme.
Inducible nitric oxide synthase, as its name suggests, is an enzyme that synthesizes nitric oxide. Nitric oxide in the brain serves a variety of functions, one of which is its role as a freely diffusing neurotransmitter.
However, nitric oxide (NO) can also react with a form of oxygen called the superoxide anion (O2-) to form highly reactive and destructive products. Usually the superoxide anion is processed into a less harmful form by the SOD1 protein.
When SOD1 is not working properly, highly reactive products of nitric oxide and the superoxide anion can accumulate and cause extensive damage. These products, such as the peroxynitrite ion, damage cells by attacking key molecular building blocks like amino acids, lipids and nucleic acids.
"Motor neurons, which are uniquely vulnerable in ALS, are also unique in that they express . . . very, very low levels [of] iNOS normally, even without any ALS pathology," Martin said. "Furthermore, and quite interestingly, even before symptoms of ALS emerge at a macro, observable level, the level of iNOS expressed in some cells increases noticeably, most specifically in the motor neurons of the spinal cord and the brainstem."
Later on, however, the greatest upregulation of iNOS is not in these cells, but rather in some microglia and astrocytes. Microglia and astrocytes are two types of neuronal support cells. Usually, they help to protect neurons or deliver nutrients and neurotransmitter precursors to neurons.
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posted 11/23/09 @ 4:57 PM EST
Quote:
"Motor neurons, which are uniquely vulnerable in ALS, are also unique in that they express . . . very, very low levels [of] iNOS normally, even without any ALS pathology," Martin said. (Continued…)
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