CD1 Gene Polymorphisms and Phenotypic Variability in X-Linked Adrenoleukodystrophy

X-linked adrenoleukodystrophy (X-ALD) is characterized by marked phenotypic variation ranging from adrenomyeloneuropathy (AMN) to childhood cerebral ALD (CCALD). X-ALD is caused by mutations in the ABCD1 gene, but no genotype-phenotype correlation has been established so far and modifier gene variants are suspected to modulate phenotypes. Specific classes of lipids, enriched in very long-chain fatty acids that accumulate in plasma and tissues from X-ALD patients are suspected to be involved in the neuroinflammatory process of CCALD. CD1 proteins are lipid- antigen presenting molecules encoded by five CD1 genes in human (CD1A-E). Association studies with 23 tag SNPs covering the CD1 locus was performed in 52 patients with AMN and 87 patients with CCALD. The minor allele of rs973742 located 4-kb downstream from CD1D was significantly more frequent in AMN patients (χ2 = 7.6; P = 0.006). However, this association was no longer significant after Bonferroni correction for multiple testing. The other polymorphisms of the CD1 locus did not reveal significant association. Further analysis of other CD1D polymorphisms did not detect stronger association with X-ALD phenotypes. Although the association with rs973742 warrants further investigations, these results indicate that the genetic variants of CD1 genes do not contribute markedly to the phenotypic variance of X-ALD

Adeno-associated virus gene therapy with cholesterol 24-hydroxylase reduces the amyloid pathology before or after the onset of amyloid plaques in mouse models of Alzheimer's disease

The development of Alzheimer's disease (AD) is closely connected with cholesterol metabolism. Cholesterol increases the production and deposition of amyloid-beta (Abeta) peptides that result in the formation of amyloid plaques, a hallmark of the pathology. In the brain, cholesterol is synthesized in situ but cannot be degraded nor cross the blood-brain barrier. The major exportable form of brain cholesterol is 24S-hydroxycholesterol, an oxysterol generated by the neuronal cholesterol 24-hydroxylase encoded by the CYP46A1 gene. We report that the injection of adeno-associated vector (AAV) encoding CYP46A1 in the cortex and hippocampus of APP23 mice before the onset of amyloid deposits markedly reduces Abeta peptides, amyloid deposits and trimeric oligomers at 12 months of age. The Morris water maze (MWM) procedure also demonstrated improvement of spatial memory at 6 months, before the onset of amyloid deposits. AAV5-wtCYP46A1 vector injection in the cortex and hippocampus of amyloid precursor protein/presenilin 1 (APP/PS) mice after the onset of amyloid deposits also reduced markedly the number of amyloid plaques in the hippocampus, and to a less extent in the cortex, 3 months after the injection. Our data demonstrate that neuronal overexpression of CYP46A1 before or after the onset of amyloid plaques significantly reduces Abeta pathology in mouse models of A

Allelic analyses of the 23 tag SNPs genotyped in CCALD and AMN patients.

a<p>: The Fisher's exact test was used for SNP with a Minor Allele Frequency (MAF)<0.10.</p>b<p>: Permutation-based empirical <i>P</i> value were calculated for SNP showing a trend of association (<i>P</i> value<0.10).</p

Tagging of the <i>CD1 locus</i>.

<p>A) Allelic association results of the tag SNPs genotyped in CCALD and AMN patients: each black dot represents a tag SNP; -log₁₀<i>P</i> is plotted for each of the 21 tag SNPs; the five <i>CD1</i> genes are indicated by black boxes; B) LD between the corresponding tag SNPs: LD is represented by shades of grey as a function of r² values (black diamond for r²≥0.90, white diamond for r² = 0). Associated tag SNPs are marked with an asterisk.</p

Allelic analyses of <i>CD1D</i> and <i>CD1B</i> variants in the CCALD and AMN patients.

a<p>: The Fisher's exact test was used for SNP with a Minor Allele Frequency (MAF)<0.10.</p>b<p>: Permutation-based empirical <i>P</i> value were calculated for SNP showing a trend of association (<i>P</i> value<0.10).</p