| dc.description.abstracteng | Although caused by distinct genetic mutations, the peroxisomal disorders X-linked
adrenoleukodystrophy (X-ALD), pseudoneonatal adrenoleukodystrophy (pseudo
NALD), and neonatal adrenoleukodystrophy (NALD) share several disease hallmarks.
Strikingly, the underlying dysfunctions are either related to generalized peroxisomal
defects or to defects in peroxisomal β-oxidation. In contrast, leukodystrophy is not a
feature of other peroxisomal disorders e.g. in α-oxidation or plasmalogen-synthesis
defects. This indicates a common pathomechanism for β-oxidation and generalized
peroxisomal defects. Further indications for this derive from mice lacking complete peroxisomal
function only in oligodendrocytes. The pattern of inflammatory subcortical
demyelination in these CnpCre/Wt*Pex5-/- mutants is reminiscent of the cerebral pathology
known from X-ALD patients lacking peroxisomal β-oxidation of very long chain fatty
acids. This led to the hypothesis that impaired β-oxidation may culminate in secondary
loss of further peroxisomal functions. So far, several mouse models with defective peroxisomal
β-oxidation were generated, but failed to develop cerebral demyelination. In
search for an appropriate model with impaired peroxisomal β-oxidation to investigate
possible secondary peroxisomal defects and subsequent pathology, aged
CnpCre/Wt*Mfp2-/- mice were analyzed. Indeed, CnpCre/Wt*Mfp2-/- mice developed demyelinating
lesions in the frontal corpus callosum when aged ≥ 16 months. This was accompanied
by reactive gliosis, lymphocyte infiltration, and behavioral alterations. Thus
CnpCre/Wt*Mfp2-/- mice proved to be suitable to study demyelination and possibly preceding
effects of impaired peroxisomal β-oxidation on peroxisomes. To facilitate oligodendrocyte
specific analysis of oligodendroglial peroxisomes novel transgenic mice
with fluorescently labeled peroxisomes in oligodendrocytes (Cnp-mEos2-PTS1) were
generated. Employing a photo-convertible fluorescent protein enabled ‘pulse-chase’
experiments to provide insight into peroxisomal biogenesis and degradation. Brain sections
from double-transgenic Cnp-mEos2-PTS1*CnpCre/Wt*Mfp2-/- mice revealed a progressively
decreasing number and increased size of peroxisomes. Alterations were
observed already at 2 months, preceding disease onset by approximately one year. At
16 months of age only 50% of peroxisomes were preserved. In vitro experiments using
primary MFP2-deficient oligodendrocytes proved a dramatically reduced peroxisomal
turnover by both, decreased degradation of pulse-labeled peroxisomes, i.e. enhanced
organelle aging, and diminished appearance of new peroxisomes. The mechanism of
this decreased organelle turnover remains elusive. Interestingly, inhibiting pexophagy
in control oligodendrocytes by use of 3-Methyladenine also blocked peroxisomal biogenesis,
which indicates tight coupling between peroxisomal biogenesis and degradation.
Together the data suggest that perturbation of peroxisomal β-oxidation in oligodendrocytes
causes secondary impairment of peroxisomal functions, which
precedes and possibly triggers cerebral demyelination. | de |