Inactivation of the peroxisomal ABCD2 transporter in the mouse leads to late-onset ataxia involving mitochondria, Golgi and endoplasmic reticulum damage

ATP-binding cassette (ABC) transporters facilitate unidirectional translocation of chemically diverse substances, ranging from peptides to lipids, across cell or organelle membranes. In peroxisomes, a subfamily of four ABC transporters (ABCD1 to ABCD4) has been related to fatty acid transport, because patients with mutations in ABCD1 (ALD gene) suffer from X-linked adrenoleukodystrophy (X-ALD), a disease characterized by an accumulation of very-long-chain fatty acids (VLCFAs). Inactivation in the mouse of the abcd1 gene leads to a late-onset neurodegenerative condition, comparable to the late-onset form of X-ALD [Pujol, A., Hindelang, C., Callizot, N., Bartsch, U., Schachner, M. and Mandel, J.L. (2002) Late onset neurological phenotype of the X-ALD gene inactivation in mice: a mouse model for adrenomyeloneuropathy. Hum. Mol. Genet., 11, 499-505.]. In the present work, we have generated and characterized a mouse deficient for abcd2, the closest paralog to abcd1. The main pathological feature in abcd2−/− mice is a late-onset cerebellar and sensory ataxia, with loss of cerebellar Purkinje cells and dorsal root ganglia cell degeneration, correlating with accumulation of VLCFAs in the latter cellular population. Axonal degeneration was present in dorsal and ventral columns in spinal cord. We have identified mitochondrial, Golgi and endoplasmic reticulum damage as the underlying pathological mechanism, thus providing evidence of a disturbed organelle cross-talk, which may be at the origin of the pathological cascad

Peroxisomal alterations in Alzheimer’s disease

In Alzheimer’s disease (AD), lipid alterations are present early during disease progression. As some of these alterations point towards a peroxisomal dysfunction, we investigated peroxisomes in human postmortem brains obtained from the cohort-based, longitudinal Vienna-Transdanube Aging (VITA) study. Based on the neuropathological Braak staging for AD on one hemisphere, the patients were grouped into three cohorts of increasing severity (stages I–II, III–IV, and V–VI, respectively). Lipid analyses of cortical regions from the other hemisphere revealed accumulation of C22:0 and very long-chain fatty acids (VLCFA, C24:0 and C26:0), all substrates for peroxisomal β-oxidation, in cases with stages V–VI pathology compared with those modestly affected (stages I–II). Conversely, the level of plasmalogens, which need intact peroxisomes for their biosynthesis, was decreased in severely affected tissues, in agreement with a peroxisomal dysfunction. In addition, the peroxisomal volume density was increased in the soma of neurons in gyrus frontalis at advanced AD stages. Confocal laser microscopy demonstrated a loss of peroxisomes in neuronal processes with abnormally phosphorylated tau protein, implicating impaired trafficking as the cause of altered peroxisomal distribution. Besides the original Braak staging, the study design allowed a direct correlation between the biochemical findings and the amount of neurofibrillary tangles (NFT) and neuritic plaques, quantified in adjacent tissue sections. Interestingly, the decrease in plasmalogens and the increase in VLCFA and peroxisomal volume density in neuronal somata all showed a stronger association with NFT than with neuritic plaques. These results indicate substantial peroxisome-related alterations in AD, which may contribute to the progression of AD pathology

The effect of a photopolymerizable poly(ε-caprolactone-co-glycolide) matrix on the cement reactions of tetracalcium phosphate and tetracalcium phosphate-monocalcium phosphate monohydrate mixtures

In this study, the influence of a biodegradable polymer matrix on the conversion of tetracalcium phosphate (TTCP) or TTCP-monocalcium phosphate monohydrate (MCPM) powders was investigated. As a reference, the properties of three calcium phosphate cements (CPCs) based on TTCP or TTCP-MCPM mixtures were discussed. Additionally, the influence of these calcium phosphate (CP) reacting powders on the polymer degradation was studied. Composites were formulated by mixing cross-linkable dimethacrylates of the 3-caprolactone/glycolide co-polymer with hydroxyethylmethacrylate, a photo-initiator and TTCP or TTCP-MCPM. The composite samples were set by visible light irradiation. CPC and composite samples were immersed in HEPES at 37 degrees C. The CPC based on TTCP converted to a carbonated apatite. Adding MCPM to the TTCP powder improved the conversion of TTCP. By varying the MCPM/TTCP ratio it was possible to tailor the conversion reactions so that an apatitic phase could be formed via intermediate products like DPC, DCPD and OCP. In the composites, a mutual interaction between the CP reacting powders and the polymer was observed. The co-polymer and its degradation products influenced the conversion reactions of the CP reacting powders. The degradation products tend to enhance the TTCP conversion after a long immersion time. The conversion of the TTCP-MCPM mixtures was retarded by the polymer matrix although the intermediate products were not altered. The basicity or acidity of the CP reacting powders and their conversion reactions were the main cause for the retarded polymer degradation, which was more pronounced when the basicity of the CP reacting powders increased

Polyphasic characterisation of Burkholderia cepacia-like isolates leading to the emended description of Burkholderia pyrrocinia

Twenty-five Burkholderia cepacia-like isolates of human and environmental origin, comprising five different recA RFLP types, were examined by using a polyphasic taxonomic approach, including recA gene sequence analysis, 16S rRNA gene sequence analysis, DNA:DNA hybridisation studies, tDNA-PCR, fatty acid analysis and biochemical analysis. The results of the present study demonstrated that twenty-three of these strains belong to Burkholderia pyrrocinia, a B. cepacia complex species thus far comprising one single soil isolate only. An emended description of Burkholderia pyrrocinia is proposed. The taxonomic status of the remaining two isolates requires further analysis

Short-chain Acyl-CoA dehydrogenase deficiency: studies in a large family adding to the complexity of the disorder

OBJECTIVE: To understand the expanding clinical and biochemical spectrum of short-chain acyl-CoA dehydrogenase (SCAD) deficiency, the impact of which is not fully understood. STUDY DESIGN: We studied a family with SCAD deficiency and determined urinary ethylmalonic acid excretion, plasma C(4)-carnitine, SCAD enzyme activity in fibroblasts and lymphocytes, DNA mutations in the SCAD gene, and clinical expression. The index patient was born prematurely and had otherwise unexplained cholestasis and hepatomegaly during the first year of life. His mother developed a hemolysis-elevated liver enzymes-low platelets (HELLP) syndrome while pregnant with the index patient. RESULTS: Two siblings had a homozygous inactivating 1138C>T mutation, whereas the father was compound heterozygous for this mutation and the common 625G>A polymorphism. There was a good correlation between the type of SCAD mutation, the residual SCAD enzyme activity, and the levels of urinary ethylmalonic acid and plasma C(4)-carnitine in each of the eight family members. Retrospective acylcarnitine analysis of the index patient's Guthrie screening card confirmed the abnormal increase of C(4)-carnitine, suggestive of SCAD deficiency. None of the family members had hypotonia, developmental delay, or episodes of ketotic hypoglycemia. CONCLUSION: Homozygosity for an inactivating SCAD mutation does not necessarily result in disease. The previously held opinion that SCAD deficiency is always a serious disorder may have been influenced by a clinical bias. Homozygosity for an inactivating 1138C>T SCAD mutation was assessed by neonatal screening of blood spot acylcarnitines. SCAD deficiency may be associated with maternal HELLP syndrom