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

Abnormalities in energy metabolism and oxidative stress accompany many neur odegenerative diseases, including progressive supranuclear palsy (PSP). Pre viously, we showed decreased activities of a mitochondrial enzyme complex, alpha -ketoglutarate dehydrogenase complex (KG-DHC), and marked increases i n tissue malondialdehyde levels in post-mortem superior frontal cortex from the patients with PSP. The current study demonstrates that KGDHC is also s ignificantly diminished (-58%) in the cerebellum from patients with PSP (n = 14), compared to age-matched control brains (n = 13). In contrast to cort ex, markers of oxidative stress, such as malondialdehyde, tyrosine nitratio n 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 measure d to determine whether the changes in KGDHC were selective. The activity of aconitase, a mitochondrial enzyme with an iron/sulfur cluster, is also sig nificantly diminished (-50%), whereas glutamate dehydrogenase activity is u nchanged. The present results suggest that the interaction of metabolic imp airment 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 pa tients with PSP. (C) 2001 Wiley-Liss, Inc.