Contributions
Abstract: 72
Type: Educational Session
Abstract Category: N/A
Multiple Sclerosis (MS) is an inflammatory demyelinating disorder of the central nervous system, initially characterised by acute relapses of neurological dysfunction followed by remission. After a variable period this is followed in the majority of patients by a slow and irreversible progression of neurological dysfunction. Histopathological examination of post-mortem tissue from progressive MS patients revealed that neuronal damage in MS cortex ranges from a subtle loss of synapses to substantial neuronal loss. Recent work by us and others has identified mitochondria as key players in the induction and progression of neuronal damage and evidence is emerging that neuronal mitochondrial defects, such as reduced expression of mitochondrial antioxidants, mitochondrial DNA deletions and decreased expression and activity of various subunits of the respiratory chain and ATP-synthase, are extensive in MS cortex. These neuronal mitochondrial defects are associated with a profound decrease in neuronal proliferator-activated receptor-γ co-activator 1α (PGC-1α), a master regulator of mitochondrial metabolism, expression in MS grey matter. In search of mechanisms contributing to neuronal mitochondrial dysfunction we have identified a profound role for tumor necrosis factor-alpha (TNF). Previous studies have found TNF production to be strongly upregulated in the cortex of progressive MS patients. Our in vitro data indicate that TNF treatment leads to marked reduction in neuronal PGC-1α expression and consequently induced neuronal mitochondrial dysfunction by enhanced free radical production and reduced ATP generation. Importantly, prolonged TNF exposure rendered neurons more vulnerable to a subsequent oxidative attack. Finally, I will present preliminary data demonstrating neuronal mitochondrial alterations in a novel MS animal model that is characterized by meningeal inflammation, cortical demyelination and robust microglial cell activation in the cortex.
Disclosure: Maarten Witte: nothing to disclose
Richard Reynolds: nothing to disclose
Jack van Horssen: nothing to disclose
Funding: National MS Society
Abstract: 72
Type: Educational Session
Abstract Category: N/A
Multiple Sclerosis (MS) is an inflammatory demyelinating disorder of the central nervous system, initially characterised by acute relapses of neurological dysfunction followed by remission. After a variable period this is followed in the majority of patients by a slow and irreversible progression of neurological dysfunction. Histopathological examination of post-mortem tissue from progressive MS patients revealed that neuronal damage in MS cortex ranges from a subtle loss of synapses to substantial neuronal loss. Recent work by us and others has identified mitochondria as key players in the induction and progression of neuronal damage and evidence is emerging that neuronal mitochondrial defects, such as reduced expression of mitochondrial antioxidants, mitochondrial DNA deletions and decreased expression and activity of various subunits of the respiratory chain and ATP-synthase, are extensive in MS cortex. These neuronal mitochondrial defects are associated with a profound decrease in neuronal proliferator-activated receptor-γ co-activator 1α (PGC-1α), a master regulator of mitochondrial metabolism, expression in MS grey matter. In search of mechanisms contributing to neuronal mitochondrial dysfunction we have identified a profound role for tumor necrosis factor-alpha (TNF). Previous studies have found TNF production to be strongly upregulated in the cortex of progressive MS patients. Our in vitro data indicate that TNF treatment leads to marked reduction in neuronal PGC-1α expression and consequently induced neuronal mitochondrial dysfunction by enhanced free radical production and reduced ATP generation. Importantly, prolonged TNF exposure rendered neurons more vulnerable to a subsequent oxidative attack. Finally, I will present preliminary data demonstrating neuronal mitochondrial alterations in a novel MS animal model that is characterized by meningeal inflammation, cortical demyelination and robust microglial cell activation in the cortex.
Disclosure: Maarten Witte: nothing to disclose
Richard Reynolds: nothing to disclose
Jack van Horssen: nothing to disclose
Funding: National MS Society