Chronic mitochondrial energy impairment produces selective striatal degeneration and abnormal choreiform movements in primates.

Abstract

Although the gene defect responsible for Huntington disease (HD) has recently been identified, the pathogenesis of the disease remains obscure. One potential mechanism is that the gene defect may lead to an impairment of energy metabolism followed by slow excitotoxic neuronal injury. In the present study we examined whether chronic administration of 3-nitropropionic acid (3-NP), an irreversible inhibitor of succinate dehydrogenase, can replicate the neuropathologic and clinical features of HD in nonhuman primates. After 3-6 weeks of 3-NP administration, apomorphine treatment induced a significant increase in motor activity as compared with saline-treated controls. Animals showed both choreiform movements, as well as foot and limb dystonia, which are characteristic of HD. More prolonged 3-NP treatment in two additional primates resulted in spontaneous dystonia and dyskinesia accompanied by lesions in the caudate and putamen seen by magnetic resonance imaging. Histologic evaluation showed that there was a depletion of calbindin neurons, astrogliosis, sparing of NADPH-diaphorase neurons, and growth-related proliferative changes in dendrites of spiny neurons similar to changes in HD. The striosomal organization of the striatum and the nucleus accumbens were spared. These findings show that chronic administration of3-NP to nonhuman primates can replicate many of the characteristic motor and histologic features of HD, further strengthening the possibility that a subtle impairment of energy metabolism may play a role in its pathogenesis.Huntington disease (HD) is an inherited neurodegenerative disease characterized by choreiform movements, cognitive impairment, and emotional disturbance. Although the gene defect in HD has recently been identified, the mechanism by which it leads to neuronal degeneration remains obscure (1). A leading hypothesis is that excitotoxicity may contribute to the pathogenesis of HD (2, 3). Studies in both rodents and primates show striking similarities between striatal lesions produced by N-methyl-D-aspartate (NMDA) agonists and the neurochemical and histologic features of HD (4-6). Further evidence in support of an NMDA excitotoxic mechanism is the finding of a preferential loss of striatal NMDA receptors, which may occur early in the disease process (7,8). One means by which slow excitotoxic neuronal death may occur is as a consequence of a defect in energy metabolism (2, 3). Disruption of ATP synthesis may lead to partial neuronal depolarization with activation of voltage-dependent NMDA receptors and secondary excitotoxic neuronal damage (9-12). UnderThe publication costs of this article were defrayed in part by page charge payment. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. §1734 solely to indicate this fact.these circumstances ambient levels of glutamate are sufficient to induce neuronal death. Several studies have reported decreased glucose metabolism and abnormalities in electron transport enzymes in HD (2). We recently obtained in ...

Mitochondrial Cyclic AMP Response Element-binding Protein (CREB) Mediates Mitochondrial Gene Expression and Neuronal Survival

“…4). In concert with previous studies demonstrating defective mitochondrial function in HD patients and transgenic mice (19,(22)(23)(24), our findings suggest that loss of mitochondrial CREB may play a role in the pathophysiology of HD. Table 1 and Fig.…”

Increased Vulnerability to 3‐Nitropropionic Acid in an Animal Model of Huntington's Disease

“…Furthermore, we recently demonstrated that creatine administration can block 3-NP-induced decreases in both phosphocreatine and ATP and exert significant neuroprotection, consistent with an effect of 3-NP on energy metabolism (Matthews et al, 1998). Following administration of 3-NP to primates, there is selective neuronal degeneration, as well as an apomorphine-inducible choreiform movement disorder that strongly mimics that seen in HD (Brouillet et al, 1995).…”

“…The finding that the HD transgenic mice show increased sensitivity to 3-NP is of interest, because 3-NP administration replicates many of the neurochemical and neuropathologic findings of HD (Beal et al, 1993;Brouillet et al, 1995). Accidental ingestion of 3-NP in humans results in selective basal ganglia lesions accompanied by delayed onset of chorea and dystonia (Ludolph et al, 1992).…”

“…Furthermore, we recently demonstrated that creatine administration can block 3-NP-induced decreases in both phosphocreatine and ATP and exert significant neuroprotection, consistent with an effect of 3-NP on energy metabolism (Matthews et al, 1998). Following administration of 3-NP to primates, there is selective neuronal degeneration, as well as an apomorphine-inducible choreiform movement disorder that strongly mimics that seen in HD (Brouillet et al, 1995).We found that the transgenic HD mice show a number of metabolic defects, including small increases in lactate and decreases in N-acetylaspartate as assessed by MRI spectroscopy (P. Klivenyi, E. Weber, B. G. Jenkins, and M. F. Beal, unpublished observations). The present experiments therefore provide direct in vivo evidence that both metabolic defects and oxidative damage may play a role in the pathogenesis of neuronal degeneration seen in transgenic HD mice.…”

Toxicity of expanded polyglutamine‐domain proteins in Escherichia coli

“…The latter possibility seems less likely in view of the toxicity of polyglutamine in COS cells [13] and in E. coli. A potential mechanism of toxicity is a quantitative or qualitative change in protein-polyglutamine domain interactions which vary as a function of polyglutamine length [30]. Polyglutamine domains can mediate protein-protein interactions by forming polar zippers.…”