Abstract
Niemann-Pick Type C (NPC) disease is an autosomal recessive neurodegenerative disorder caused in most cases by mutations in the NPC1 gene. NPC1-deficiency is characterized by late endosomal accumulation of cholesterol, impaired cholesterol homeostasis, and a broad range of other cellular abnormalities. Although neuronal abnormalities and glial activation are observed in nearly all areas of the brain, the most severe consequence of NPC1-deficiency is a near complete loss of Purkinje neurons in the cerebellum. The link between cholesterol trafficking and NPC pathogenesis is not yet clear; however, increased oxidative stress in symptomatic NPC disease, increases in mitochondrial cholesterol, and alterations in autophagy/mitophagy suggest that mitochondria play a role in NPC disease pathology. Alterations in mitochondrial function affect energy and neurotransmitter metabolism, and are particularly harmful to the central nervous system. To investigate early metabolic alterations that could affect NPC disease progression, we performed metabolomics analyses of different brain regions from age-matched wildtype and Npc1 -/- mice at pre-symptomatic, early symptomatic and late stage disease by 1H-NMR spectroscopy. Metabolic profiling revealed markedly increased lactate and decreased acetate/acetyl-CoA levels in Npc1 -/- cerebellum and cerebral cortex at all ages. Protein and gene expression analyses indicated a pre-symptomatic deficiency in the oxidative decarboxylation of pyruvate to acetyl-CoA, and an upregulation of glycolytic gene expression at the early symptomatic stage. We also observed a pre-symptomatic increase in several indicators of oxidative stress and antioxidant response systems in Npc1 -/- cerebellum. Our findings suggest that energy metabolism and oxidative stress may present additional therapeutic targets in NPC disease, especially if intervention can be started at an early stage of the disease.
Highlights
Niemann-Pick Type C (NPC) disease is a fatal, autosomal recessive neurodegenerative disease caused in 95% of cases by mutations in the NPC1 gene and in the remaining cases by mutations in NPC2
The decreased mRNA levels of neuronal Eno2 and Aralar1 in Npc1-/- cerebellum at 7 weeks of age (Fig 3G and 5J) likely reflected Purkinje neuron death, as mRNA levels of the Purkinje cell marker calbindin (Calb1) and of the neuron-specific neurofilament heavy peptide (Nefh) were decreased by 60% and 25% respectively at this age (Fig 5K and L). These findings demonstrated that alterations in cerebellar glucose metabolism developed early in NPC disease, and could already be detected in 3-week old, pre-symptomatic Npc1-/- mice
Using an unbiased metabolomics strategy and targeted gene expression analyses of wildtype and Npc1-/brain tissue, we found i) significant alterations in glucose and pyruvate metabolism that suggested a pre-symptomatic decrease in the oxidative metabolism of glucose, and a compensatory increase in glycolysis with disease progression, and ii) a pre-symptomatic activation of astrocytic antioxidant response systems, which suggests that oxidative stress plays a key role early in NPC disease pathogenesis
Summary
Niemann-Pick Type C (NPC) disease is a fatal, autosomal recessive neurodegenerative disease caused in 95% of cases by mutations in the NPC1 gene and in the remaining cases by mutations in NPC2. The loss of either NPC1 or NPC2 leads to the endo/lysosomal accumulation of unesterified cholesterol, an impaired cholesterol homeostatic response and a wide range of other cellular abnormalities, such as decreased oxysterol production, alterations in calcium homeostasis and autophagy, increased oxidative stress and inflammatory responses [4,5,6,7,8,9]. Neuronal cholesterol accumulation begins at early, pre-symptomatic stages of the disease, and mobilization of endosomal cholesterol in vitro or in vivo can prevent many of the cellular abnormalities and symptoms of NPC disease [15,16,17,18,19]. The defect in cholesterol trafficking causes many, if not all, cellular abnormalities observed in NPC disease, relatively little is known about the cellular mechanisms leading to neuronal dysfunction and neurodegeneration
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