Neuronal Dysfunction Associated with Cholesterol Deregulation

Abstract

Cholesterol metabolism is crucial for cells and, in particular, its biosynthesis in the central nervous system occurs in situ, and its deregulation involves morphological changes that cause functional variations and trigger programmed cell death. The pathogenesis of rare diseases, such as Mevalonate Kinase Deficiency or Smith–Lemli–Opitz Syndrome, arises due to enzymatic defects in the cholesterol metabolic pathways, resulting in a shortage of downstream products. The most severe clinical manifestations of these diseases appear as neurological defects. Expanding the knowledge of this biological mechanism will be useful for identifying potential targets and preventing neuronal damage. Several studies have demonstrated that deregulation of the cholesterol pathway induces mitochondrial dysfunction as the result of respiratory chain damage. We set out to determine whether mitochondrial damage may be prevented by using protective mitochondria-targeted compounds, such as MitoQ, in a neuronal cell line treated with a statin to induce a biochemical block of the cholesterol pathway. Evidence from the literature suggests that mitochondria play a crucial role in the apoptotic mechanism secondary to blocking the cholesterol pathway. Our study shows that MitoQ, administered as a preventive agent, could counteract the cell damage induced by statins in the early stages, but its protective role fades over time.

The Complex Interplay between Lipids, Immune System and Interleukins in Cardio-Metabolic Diseases

“…In addition to these forms of “systemic” hypocholesterolemia, there can be “tissue” hypocholesterolemias, such as in patients with inherited defects in cholesterol biosynthesis [97], where circulating cholesterol is normal or slightly low but brain cholesterol can be virtually absent. This is due to the fact that all the cholesterol contained in the brain is the result of an in situ synthesis because the blood-brain barrier does not allow the passage of circulating lipoproteins [98,99,100]. Therefore, when there is a defect in cholesterol biosynthesis and cholesterol synthesis is impaired, intermediate metabolites accumulate in the central nervous system and cause apoptosis, autophagy, and NLRP3-inflammasome activation [97,100,101,102] (Figure 3), leading to neuroinflammation [98,99,103].…”

“…This is due to the fact that all the cholesterol contained in the brain is the result of an in situ synthesis because the blood-brain barrier does not allow the passage of circulating lipoproteins [98,99,100]. Therefore, when there is a defect in cholesterol biosynthesis and cholesterol synthesis is impaired, intermediate metabolites accumulate in the central nervous system and cause apoptosis, autophagy, and NLRP3-inflammasome activation [97,100,101,102] (Figure 3), leading to neuroinflammation [98,99,103]. The damage to the central nervous system presents with psychomotor retardation, developmental delay, structural brain malformations, multiple congenital anomalies, microcephaly, autism and other behavioral disorders [97].…”

MitoQ Is Able to Modulate Apoptosis and Inflammation

“…These dysregulations are more easily detectable in the central nervous system, since this area represents a system closed to cholesterol synthesis [ 17 ]. It is well known that statins, such as lovastatin, are able to induce apoptosis in neuronal cell lines and that the mevalonate prevents the programmed cell death induced by the blockade of this pathway [ 18 , 19 ].…”

Thymoquinone Protects Neurons in the Cerebellum of Rats through Mitigating Oxidative Stress and Inflammation Following High-Fat Diet Supplementation

“…Afflictions to the brain are linked with metabolic alterations generated by obesity. These afflictions could prompt neuronal death, either by apoptosis or cell necrosis, in addition to changes in the neuron’s synaptic plasticity [ 4 , 5 ]. Obesity now is ranked as the fifth leading cause of death worldwide, and its global spread is alarming [ 6 ].…”