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

Abstract

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.

Non‐invasive detection of neurochemical changes prior to overt pathology in a mouse model of spinocerebellar ataxia type 1

“…The reduced levels of tCho detected in the Sca1 154Q/2Q mice may also reflect changes in phospholipid metabolism of cell membranes. Namely, disturbances in membrane phospholipid metabolism have been suggested based on post-mortem analysis of brain tissue from patients with SCA1 (Eder et al 1998; Ross et al 2000). On the other hand, other detectable metabolites involved in phospholipid metabolism ( myo -Ins and PE) did not change with disease progression in the cerebella of the Sca1 154Q/2Q mice.…”

Differences between Spinocerebellar Ataxias and Multiple System Atrophy-Cerebellar Type on Proton Magnetic Resonance Spectroscopy

“…[13]–[17]. However, most of the reports only focused on limited subtype of SCA or only described the differences between patients and healthy controls.…”

Highlighting anatomical sub-structures in rat brain tissue using lipid imaging

“…Indeed, alterations in the level of SM are common in lysosomal diseases such as Niemann-Pick, 10,11 in ammonia intoxication 12 and brain ischemia, 13 while changes in PC metabolism have been observed in pathological conditions such as Alzheimer disease 14 and ataxia. 15,16 …”