Membrane Metabolism

Autism, membrane metabolism and calcium homeostasis

Smith-Lemli-Opitz Syndrome (SLOS) is a rare genetic condition of impaired cholesterol biosynthesis, with most of affected individuals simultaneoulsy exhibiting at least some of the symptoms of autism. The figures on the rates of formal autism diagnosis in individuals with SLOS vary but appear to be somewhere between 50-75 percent, among the highest of single gene disorders associated with autism [16761297]. While supplementing dietary cholesterol frequently eliminates or ameliorates many of the feeding and growth problems of SLOS, it has been observed recently the autistic behaviors of children with SLOS can also be reduced or even eliminated by treatment with supplementary dietary cholesterol. In addition to behavioural and language-delay problems, individuals with SLOS often suffer from several gastrointestinal problems, including severe reflux and constipation, immune deficiency and sleep problems.

Disturbances in membrane sterol content in SLOS is thought to directly contribute to various cellular abnormalities in observed in this disease, which include significantly increased calcium permeability as well as reduced folate uptake (see Oxidative Stress). Most interestingly, partial restoration of the excessive calcium influx pathway was observed following cholesterol enrichment [16258167]. Increasing evidence indicates that membrane cholesterol is capable of modulating function of voltage gated calcium channels. Caveolae, including caveolae-like plasma domains in neurons, and transverse (T-) tubules are membrane lipid-raft structures rich in caveolin, cholesterol and glycosphingolipids, as well as VGCC. Recent results have shown that a depletion of membrane cholesterol alters caveolae and T-tubules. Cholesterol and LTCC occupy a similar molecular location in the membrane. In one study application of a a cholesterol-sequestering drug resulted in significant reduction in caveolae and T-tubule areas and to a significant reduction of LTCC current, suggesting that membrane cholesterol content modulates their function, and that both lowered and excessive cholesterol levels can modulate calcium currents [14724204, 2054935]. This is proposed to be one possible mechanism behind the observed reduction in autistic symptoms in SLOS following supplementation of dietary cholesterol. Another possible mechanism to be taken into consideration is the effect of cholesterol on several serotonin receptors and G-protein and ligand bindings of those receptors (see Neurotransmitters).

In another study the addition of Caveolin-1 to cultured neurons resulted in increased levels of membrane cholesterol and reduction in calcium currents, thus showing that caveolin-1 also influences neuronal VGCC activity [16040758].

Following the above findings, it is proposed that the opposite effect might exist, whereas dysregulation of VGCC could under certain conditions directly influence the membrane structure, including the synthesis and/or levels of cholesterol and caveolin [11353331]. In support of this hypothesis is the finding from human fertility studies demonstrating that cholesterol synthesis can be significantly increased in sperm treated with nifedipine, a calcium channel antagonist [link].

Abnormalities of cholesterol metabolism have been observed in more common forms of autism, with substantial numbers of individuals showing lowered levels as compared to controls [16874769], while elevated levels of cholestorol have been observed in individuals with Asperger's syndrome [17123635]. In addition to cholestorol levels, results of a study investigating brain high energy phosphate and membrane phospholipid metabolism provided further evidence of undersynthesis and increased degradation of brain membranes in autism. It was observed that membrane building blocks decreased, and levels of membrane breakdown products increased parallel to a decline test performance abilities in subjects with autism [8373914].

In addition to the above, it is worth mentioning that one of the downstream reactions in neurons following elevation in the levels of intercellular calcium is the activation of several lipases, proteases, and endonucleases that attack the structural integrity of the cell. Calcium also activates phospholipase C, which promotes a progressive breakdown in the phospholipid components of the both plasma and intercellular membranes.