Abstract
Pyruvate dehydrogenase (PDH) complex (PDC) deficiency is an inborn error of pyruvate metabolism causing a variety of neurologic manifestations. Systematic analyses of development of affected brain structures and the cellular processes responsible for their impairment have not been performed due to the lack of an animal model for PDC deficiency. METHODS: In the present study we investigated a murine model of systemic PDC deficiency by interrupting the X-linked Pdha1 gene encoding the α subunit of PDH to study its role on brain development and behavioral studies. RESULTS: Male embryos died prenatally but heterozygous females were born. PDC activity was reduced in the brain and other tissues in female progeny compared to age-matched control females. Immunohistochemical analysis of several brain regions showed that approximately 40% of cells were PDH−. The oxidation of glucose to CO2 and incorporation of glucose-carbon into fatty acids were reduced in brain slices from 15 day-old PDC-deficient females. Histological analyses showed alterations in several structures in white and gray matters in 35 day-old PDC-deficient females. Reduction in total cell number and reduced dendritic arbors in Purkinje neurons were observed in PDC-deficient females. Furthermore, cell proliferation, migration and differentiation into neurons by newly generated cells were reduced in the affected females during pre- and postnatal periods. PDC-deficient mice had normal locomotor activity in a novel environment but displayed decreased startle responses to loud noises and there was evidence of abnormal pre-pulse inhibition of the startle reflex. CONCLUSIONS: The results show that a reduction in glucose metabolism resulting in deficit in energy production and fatty acid biosynthesis impairs cellular differentiation and brain development in PDC-deficient mice.
Highlights
The pyruvate dehydrogenase complex (PDC) plays a pivotal role in glucose metabolism by converting pyruvate to acetyl-CoA and linking the glycolytic pathway with the tricarboxylic acid cycle
PCR analysis of genomic DNA from brain, liver, heart and skeletal muscle of Cre-positive (PDCdeficient) females indicated the deletion of exon8 (400 bp; Pdha1Dex8; from maternally-derived chromosome X) and wild-type Pdha1 (700 bp; Pdha1wt; from paternally-derived chromosome X) alleles and the presence of Cre transgene (240 bp) in these tissues (Fig. 1A, B)
PDC deficiency results in malformation of brain structures and often severe neurological symptoms in PDCdeficient patients [8,10,11], the mechanisms responsible for aberrant brain development in affected patients remains largely uncharacterized
Summary
The pyruvate dehydrogenase complex (PDC) plays a pivotal role in glucose metabolism by converting pyruvate to acetyl-CoA and linking the glycolytic pathway with the tricarboxylic acid cycle. Mammalian PDC, a multienzyme mitochondrial complex, is composed of multiple copies of three catalytic components [pyruvate dehydrogenase (PDH; a2b2 tetramer), dihydrolipoamide acetyltransferase and dihydrolipoamide dehydrogenase], a noncatalytic component dihydrolipoamide dehydrogenase-binding protein and two regulatory components [pyruvate dehydrogenase kinases (four isoenzymes) and phosphopyruvate dehydrogenase phosphatases (two isoenzymes)] [1,2]. All of the catalytic and regulatory subunits are encoded by single copies of autosomal genes with the exception of the a subunit of PDH. To allow a high rate of aerobic glucose oxidation, adult mammalian brain maintains a high proportion (,70%) of PDC in the dephosphorylated (active) form [5]. During the prenatal and early postnatal periods PDC plays a central role in lipid biosynthesis from glucose in the brain [6]
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