Abnormal activity of membrane phospholipid synthetic enzymes in the brain of patients with Friedreich's ataxia and spinocerebellar atrophy type-1.

Much evidence, derived from biochemical studies of both blood and autopsied brain, has suggested that phospholipid metabolism is abnormal in patients with Friedreich's ataxia (FA), a disorder characterized by severe neuronal loss in the spinal cord and lower brain stem with no, or only modest, damage in other brain regions. To establish the cause of our recent finding of reduced brain levels of phospholipids in FA, we assayed activities of 10 phospholipid-metabolizing enzymes in the autopsied cerebellar cortex of patients with the disorder and, for comparison, in a group of patients with spinocerebellar ataxia type 1 (SCA-1), a disease characterized, unlike FA, by marked neuronal loss in the cerebellar cortex. Enzyme activities were also measured in four brain areas which are relatively unaffected morphologically in both FA and SCA-1. We found that ethanolamine kinase activity was increased in multiple brain regions of patients with FA (increased 31%-137%) and, more modestly, in SCA-1 (increased 39%-60%), suggesting a nonspecific enhancement of phosphoethanolamine production in both disorders. In contrast, the activity of phosphoethanolamine cytidylyltransferase (PECT), the rate-limiting enzyme of phosphatidylethanolamine synthesis, was significantly and markedly decreased by 35%-78% in the cerebellar, frontal, and occipital cortices of patients with FA but was normal in SCA-1. Reduced PECT activity in FA may explain the lower brain levels of phosphatidylethanolamine in the disorder. Moreover, because decreased PECT activity in FA occurs in brain regions having no, or only modest, morphologic damage, this may represent a systemic change consequent to the frataxin gene defect. Our data also suggest that therapeutic intervention in FA designed to increase synthesis of membrane phospholipids may warrant further investigation.