Mitochondrial impairment in the cerebellum of the patients with progressive supranuclear palsy

Abstract

Abnormalities in energy metabolism and oxidative stress accompany many neurodegenerative diseases, including progressive supranuclear palsy (PSP). Previously, we showed decreased activities of a mitochondrial enzyme complex, alpha-ketoglutarate dehydrogenase complex (KGDHC), and marked increases in tissue malondialdehyde levels in post-mortem superior frontal cortex from the patients with PSP. The current study demonstrates that KGDHC is also significantly diminished (-58%) in the cerebellum from patients with PSP (n = 14), compared to age-matched control brains (n = 13). In contrast to cortex, markers of oxidative stress, such as malondialdehyde, tyrosine nitration or general protein carbonyl modification, did not increase in cerebellum. Furthermore, the protein levels of the individual components of KGDHC did not decline. The activities of two other mitochondrial enzymes were measured to determine whether the changes in KGDHC were selective. The activity of aconitase, a mitochondrial enzyme with an iron/sulfur cluster, is also significantly diminished (-50%), whereas glutamate dehydrogenase activity is unchanged. The present results suggest that the interaction of metabolic impairment and oxidative stress is region-specific in PSP brain. In cerebellum, reductions in KGDHC occur in the absence of increases in common measures of oxidative stress, and may underlie the metabolic deficits and contribute to pathological and clinical manifestation related to the cerebellum in patients with PSP.

Neuronal degeneration and mitochondrial dysfunction

“…Postmortem PSP brains had an increased content of malondialdehyde, a marker of lipid peroxidation, and reduced activity of α-ketoglutarate dehydrogenase, the rate-limiting enzyme of the Krebs cycle, but they also had normal respiratory chain activities (45,46). While it is conceivable that a combination of mitochondrial dysfunction and oxidative stress could generate a vicious cycle leading to further oxidative damage and neuronal degeneration, at this point it is difficult to hypothesize a model consistent with both OXPHOS defects in muscle and normal complex I and IV activities in brain, or to explain why the Krebs cycle should be affected in particular.…”

Thiamine deficiency induces endoplasmic reticulum stress in neurons

“…TD-induced neuronal loss accompanies a mild and chronic impairment of oxidative metabolism as well as inflammatory responses and glial activation (Ke and Gibson, 2004). Selective cell death, inflammation, glial activation and abnormalities in oxidative metabolism are common in many aging-related neurodegenerative diseases, such as Alzheimer's disease (AD) (Gibson and Zhang, 2001), Parkinson's disease (PD) (Schwab et al, 1996) and progressive supranuclear palsy (Park et al, 2001). The neurological disorder that is most clearly associated with TD in humans is Wernicke-Korsakoff syndrome (WKS), which is characterized by severe memory loss, cholinergic deficits and selective cell death in specific brain regions (Victor et al, 1989;Todd and Butterworth, 1999;Calingasan and Gibson, 2000;Ke et al, 2003).…”

Responses of the mitochondrial alpha-ketoglutarate dehydrogenase complex to thiamine deficiency may contribute to regional selective vulnerability

“…Thiamine deficiency (TD) in rodents induces mild oxidative stress, microglial activation, selective neuronal cell death, diminished energy metabolism and behavioral abnormalities (Langlais et al, 1997;Calingasan et al, 1999Calingasan et al, , 2000Hakim and Pappius, 1981;Gibson et al, 1982;Freeman et al, 1987) that model important aspects of a number of neurodegenerative diseases including Alzheimer's disease (AD) Zhang, 2001, 2002a), Parkinson's disease (PD) (Schwab et al, 1996;Gibson et al, 2003), progressive supranuclear palsy (Park et al, 2001) and Wernicke-Korsakoff's syndrome (Victor et al, 1989). Diminished activities of thiamine dependent-enzymes such as the α-ketoglutarate dehydrogenase complex (KGDHC) have been consistently observed in brains of TD animal models and in post mortem brains of humans with age-related diseases (Sheu et al, 1998;Gibson et al, 1999;Mastrogiacoma et.…”

“…A decline in KGDHC activity would be expected to diminish metabolism and promote neurodegeneration. KGDHC activity can be inhibited by multiple oxidants, and is one of the enzymes that are most sensitive to oxidative stress (Albers et al, 2000;Park et al, 2001). Oxidant-induced reductions in production of NADH by mitochondria are due to effects on KGDHC (Tretter and Adam-Vizi, 2000).…”