Pathogenesis of peroxisomal deficiency disorders (Zellweger syndrome) may be mediated by misregulation of the GABAergic system via the diazepam binding inhibitor

Abstract

Background: Zellweger syndrome (ZS) is a fatal inherited disease caused by peroxisome biogenesis deficiency. Patients are characterized by multiple disturbances of lipid metabolism, profound hypotonia and neonatal seizures, and distinct craniofacial malformations. Median live expectancy of ZS patients is less than one year. While the molecular basis of peroxisome biogenesis and metabolism is known in considerable detail, it is unclear how peroxisome deficiency leads to the most severe neurological symptoms. Recent analysis of ZS mouse models has all but invalidated previous hypotheses.

Hypothesis: We suggest that a regulatory rather than a metabolic defect is responsible for the drastic impairment of brain function in ZS patients.

Testing the hypothesis: Using microarray analysis we identify diazepam binding inhibitor/acyl-CoA binding protein (DBI) as a candidate protein that might be involved in the pathogenic mechanism of ZS. DBI has a dual role as a neuropeptide antagonist of GABA(A) receptor signaling in the brain and as a regulator of lipid metabolism. Repression of DBI in ZS patients could result in an overactivation of GABAergic signaling, thus eventually leading to the characteristic hypotonia and seizures. The most important argument for a misregulation of GABA(A) in ZS is, however, provided by the striking similarity between ZS and "benzodiazepine embryofetopathy", a malformation syndrome observed after the abuse of GABA(A) agonists during pregnancy.

Implications of the hypothesis: We present a tentative mechanistic model of the effect of DBI misregulation on neuronal function that could explain some of the aspects of the pathology of Zellweger syndrome.

Figure 1

Molecular conditions leading to Zellweger-like syndromes in human and mouse. Biochemical and pathological consequences that are not common to all disorders are indicated. PEXn = any of the peroxisome biogenesis proteins that can be mutated in classical Zellweger syndrome. MFP1/2 = multifunctional proteins of peroxisomal beta-oxidation. DHAPAT = dihydroxyacetone phosphate acyl transferase. VLCFAs = very long-chain fatty acids. DHA = docosahexaenoic acid.

Figure 2

Possible regulatory network leading to disturbed GABAergic signaling in peroxisome-deficient patients. Arrows indicate the predicted direction of change in the patients. See text for details.