11 research outputs found
ACBD5 deficiency causes a defect in peroxisomal very long-chain fatty acid metabolism
Background
Acyl-CoA binding domain containing protein 5 (ACBD5) is a peroxisomal membrane protein with a
cytosolic acyl-CoA binding domain. Because of its acyl-CoA binding domain, ACBD5 has been
assumed to function as an intracellular carrier of acyl-CoA esters. In addition, a role for ACBD5 in
pexophagy has been suggested. However, the precise role of ACBD5 in peroxisomal metabolism
and/or functioning has not yet been established. Previously, a genetic ACBD5 deficiency was
identified in three siblings with retinal dystrophy and white matter disease. We identified a pathogenic
mutation in ACBD5 in another patient and studied the consequences of the ACBD5 defect in patient
material and in ACBD5-deficient HeLa cells to uncover this role.
Methods
We studied a girl who presented with progressive leukodystrophy, syndromic cleft palate, ataxia and
retinal dystrophy. We performed biochemical, cell biological and molecular studies in patient material
and in ACBD5-deficient HeLa cells generated by CRISPR-Cas9 genome editing.
Results
We identified a homozygous deleterious indel mutation in ACBD5, leading to complete loss of ACBD5
protein in the patient. Our studies showed that ACBD5 deficiency leads to accumulation of very longchain
fatty acids (VLCFAs) due to impaired peroxisomal beta-oxidation. No effect on pexophagy was
found.
Conclusions
Our investigations strongly suggest that ACBD5 plays an important role in sequestering C26-CoA in
the cytosol and thereby facilitates transport into the peroxisome and subsequent beta-oxidation.
Accordingly, ACBD5 deficiency is a novel single peroxisomal enzyme deficiency caused by impaired
VLCFA metabolism and leading to retinal dystrophy and white matter disease.Supported in part by funding through the Marie Curie Initial Training Networks (ITN) action to
KDF, MS and HRW (FP7-2012-PERFUME-316723). MS is supported by the Biotechnology and
Biological Sciences Research Council (BB/K006231/1; BB/N01541X/1)
Corporate philanthropy through the lens of ethical subjectivity
The dynamic organisational processes in businesses dilute the boundaries between the individual, organisational, and societal drivers of corporate philanthropy. This creates a complex framework in which charitable project selection occurs. Using the example of European tour operators, this study investigates the mechanisms through which companies invest in charitable projects in overseas destinations. Inextricably linked to this is the increasing contestation by local communities as to how they are able to engage effectively with tourism in order to realise the benefits tourism development can bring. This research furthers such debates by exploring the processes through which tour operators facilitate community development through charitable giving. Findings show, with no formal frameworks in existence, project selection depends upon emergent strategies that connect the professional with the personal, with trust being positioned as a central driver of these informal processes. Discretionary responsibilities are reworked through business leaders’ commitment to responsible business practises and the ethical subjectivity guiding these processes