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Fig. 7.5 Microscopic and kinetic studies of energy metabolism in K4 cells. (a)
Fluorescence
image of K4 cells expressing EGFP-TPPP/p25 fusion protein; nuclei are stained with DAPI. (b and
c) Phase-contrast images of SK-N-MC (mother) cells (b) and K4 cells (
stable clone
) stained by
tetramethylrhodamine ethyl ester for visualization of hyperpolarization of mitochondrial mem-
brane (
red
). (Modified Fig.5 from Orosz et al.
2004
)
CAG trinucleotide repeat into the gene encoding the N-terminal segment of the
huntingtin protein. This polyglutamine tail is sticky and binds to GAPDH, a
moonlighting glycolytic enzyme; this binding is probably responsible for the partial
inactivation of this dehydrogenase as detected in the inclusion-containing region of
transgene mice. In fact, energy metabolism in the disease produced by this mutation
affects brain regions (as determined by immunohistochemistry) through changes in
the ATP-producing systems of the cytosolic and mitochondrial compartments. In
contrast to most of the speculation in the literature, our results showed that the
neuronal damage in HD tissue was associated with increased energy metabolism at
the tissue level leading to increased ATP concentration (Olah et al.
2008
). More-
over, an increased conversion of glucose into lactate occurred in cytosolic extracts
from the HD brain tissue. A mathematical model of the glycolytic pathway using
the measured kinetic parameters of the individual enzymes and the well-established
rate equations could simulate glycolytic fluxes in control and affected tissue of the
transgene mice (Fig.
7.6
). Data analysis from these comparative studies suggested a
mechanism that might account for the observed effects. In the case of HD, GAPDH
may be in closer proximity (perhaps because of binding of the enzyme to
huntingtin) to aldolase thereby facilitating channeling between these enzymes.
Hence, the association between these proteins would result in both an increased
energy metabolism and the formation of pathological inclusions leading to neuronal
damage.
The multifactorial character of molecular-conformational related diseases such
as in the interrelationship between the etiology of metabolic and neurological
disorders has been elucidated. Triosephosphate isomerase deficiency is an autoso-
mal recessive multisystemic genetic disease coupled with hemolytic anemia and
neurological disorder frequently leading to death in early childhood. Recent data
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