I
J Neurol Sci. 2005 May 13; [Epub ahead of print] Related Articles,
Links
Oxidative stress, mitochondrial dysfunction and cellular stress
response in Friedreich's ataxia.
Calabrese V, Lodi R, Tonon C, D'Agata V, Sapienza M, Scapagnini G,
Mangiameli A, Pennisi G, Stella AM, Butterfield DA.
Section of Biochemistry and Molecular Biology, Department of Chemistry,
Faculty of Medicine, University of Catania, Catania, Viale Andrea Doria
6, 95100 Catania, Italy.
There is significant evidence that the pathogenesis of several
neurodegenerative diseases, including Parkinson's disease, Alzheimer's
disease, Friedreich's ataxia (FRDA), multiple sclerosis and amyotrophic
lateral sclerosis, may involve the generation of reactive oxygen
species (ROS) and/or reactive nitrogen species (RNS) associated with
mitochondrial dysfunction. The mitochondrial genome may play an
essential role in the pathogenesis of these diseases, and evidence for
mitochondria being a site of damage in neurodegenerative disorders is
based in part on observed decreases in the respiratory chain complex
activities in Parkinson's, Alzheimer's, and Huntington's disease. Such
defects in respiratory complex activities, possibly associated with
oxidant/antioxidant imbalance, are thought to underlie defects in
energy metabolism and induce cellular degeneration. The precise
sequence of events in FRDA pathogenesis is uncertain. The impaired
intramitochondrial metabolism with increased free iron levels and a
defective mitochondrial respiratory chain, associated with increased
free radical generation and oxidative damage, may be considered
possible mechanisms that compromise cell viability. Recent evidence
suggests that frataxin might detoxify ROS via activation of glutathione
peroxidase and elevation of thiols, and in addition, that decreased
expression of frataxin protein is associated with FRDA. Many approaches
have been undertaken to understand FRDA, but the heterogeneity of the
etiologic factors makes it difficult to define the clinically most
important factor determining the onset and progression of the disease.
However, increasing evidence indicates that factors such as oxidative
stress and disturbed protein metabolism and their interaction in a
vicious cycle are central to FRDA pathogenesis. Brains of FRDA patients
undergo many changes, such as disruption of protein synthesis and
degradation, classically associated with the heat shock response, which
is one form of stress response. Heat shock proteins are proteins
serving as molecular chaperones involved in the protection of cells
from various forms of stress. In the central nervous system, heat shock
protein (HSP) synthesis is induced not only after hyperthermia, but
also following alterations in the intracellular redox environment. The
major neurodegenerative diseases, Alzheimer's disease (AD), Parkinson's
disease (PD), amyotrophic lateral sclerosis (ALS), multiple sclerosis
(MS), Huntington's disease (HD) and FRDA are all associated with the
presence of abnormal proteins. Among the various HSPs, HSP32, also
known as heme oxygenase I (HO-1), has received considerable attention,
as it has been recently demonstrated that HO-1 induction, by generating
the vasoactive molecule carbon monoxide and the potent antioxidant
bilirubin, could represent a protective system potentially active
against brain oxidative injury. Given the broad cytoprotective
properties of the heat shock response there is now strong interest in
discovering and developing pharmacological agents capable of inducing
the heat shock response. This may open up new perspectives in medicine,
as molecules inducing this defense mechanism appear to be possible
candidates for novel cytoprotective strategies. In particular,
manipulation of endogenous cellular defense mechanisms, such as the
heat shock response, through nutritional antioxidants, pharmacological
compounds or gene transduction, may represent an innovative approach to
therapeutic intervention in diseases causing tissue damage, such as
neurodegeneration.
PMID: 15896810 [PubMed - as supplied by publisher]
--------------------------------------------------------------------------------
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Tom
Jesus Was A Vegetarian!
http://jesuswasavegetarian.7h.com
Man Is A Herbivore!
http://pages.ivillage.com/ironjustice/manisaherbivore
DEAD PEOPLE WALKING
http://pages.ivillage.com/ironjustice/deadpeoplewalking
Links
Oxidative stress, mitochondrial dysfunction and cellular stress
response in Friedreich's ataxia.
Calabrese V, Lodi R, Tonon C, D'Agata V, Sapienza M, Scapagnini G,
Mangiameli A, Pennisi G, Stella AM, Butterfield DA.
Section of Biochemistry and Molecular Biology, Department of Chemistry,
Faculty of Medicine, University of Catania, Catania, Viale Andrea Doria
6, 95100 Catania, Italy.
There is significant evidence that the pathogenesis of several
neurodegenerative diseases, including Parkinson's disease, Alzheimer's
disease, Friedreich's ataxia (FRDA), multiple sclerosis and amyotrophic
lateral sclerosis, may involve the generation of reactive oxygen
species (ROS) and/or reactive nitrogen species (RNS) associated with
mitochondrial dysfunction. The mitochondrial genome may play an
essential role in the pathogenesis of these diseases, and evidence for
mitochondria being a site of damage in neurodegenerative disorders is
based in part on observed decreases in the respiratory chain complex
activities in Parkinson's, Alzheimer's, and Huntington's disease. Such
defects in respiratory complex activities, possibly associated with
oxidant/antioxidant imbalance, are thought to underlie defects in
energy metabolism and induce cellular degeneration. The precise
sequence of events in FRDA pathogenesis is uncertain. The impaired
intramitochondrial metabolism with increased free iron levels and a
defective mitochondrial respiratory chain, associated with increased
free radical generation and oxidative damage, may be considered
possible mechanisms that compromise cell viability. Recent evidence
suggests that frataxin might detoxify ROS via activation of glutathione
peroxidase and elevation of thiols, and in addition, that decreased
expression of frataxin protein is associated with FRDA. Many approaches
have been undertaken to understand FRDA, but the heterogeneity of the
etiologic factors makes it difficult to define the clinically most
important factor determining the onset and progression of the disease.
However, increasing evidence indicates that factors such as oxidative
stress and disturbed protein metabolism and their interaction in a
vicious cycle are central to FRDA pathogenesis. Brains of FRDA patients
undergo many changes, such as disruption of protein synthesis and
degradation, classically associated with the heat shock response, which
is one form of stress response. Heat shock proteins are proteins
serving as molecular chaperones involved in the protection of cells
from various forms of stress. In the central nervous system, heat shock
protein (HSP) synthesis is induced not only after hyperthermia, but
also following alterations in the intracellular redox environment. The
major neurodegenerative diseases, Alzheimer's disease (AD), Parkinson's
disease (PD), amyotrophic lateral sclerosis (ALS), multiple sclerosis
(MS), Huntington's disease (HD) and FRDA are all associated with the
presence of abnormal proteins. Among the various HSPs, HSP32, also
known as heme oxygenase I (HO-1), has received considerable attention,
as it has been recently demonstrated that HO-1 induction, by generating
the vasoactive molecule carbon monoxide and the potent antioxidant
bilirubin, could represent a protective system potentially active
against brain oxidative injury. Given the broad cytoprotective
properties of the heat shock response there is now strong interest in
discovering and developing pharmacological agents capable of inducing
the heat shock response. This may open up new perspectives in medicine,
as molecules inducing this defense mechanism appear to be possible
candidates for novel cytoprotective strategies. In particular,
manipulation of endogenous cellular defense mechanisms, such as the
heat shock response, through nutritional antioxidants, pharmacological
compounds or gene transduction, may represent an innovative approach to
therapeutic intervention in diseases causing tissue damage, such as
neurodegeneration.
PMID: 15896810 [PubMed - as supplied by publisher]
--------------------------------------------------------------------------------
Who loves ya.
Tom
Jesus Was A Vegetarian!
http://jesuswasavegetarian.7h.com
Man Is A Herbivore!
http://pages.ivillage.com/ironjustice/manisaherbivore
DEAD PEOPLE WALKING
http://pages.ivillage.com/ironjustice/deadpeoplewalking