α‐Synuclein abnormalities in mouse models of peroxisome biogenesis disorders

Abstract

Abstractalpha-Synuclein (αS) is a presynaptic protein implicated in Parkinson's disease (PD). Growing evidence implicates mitochondrial dysfunction, oxidative stress and αS-lipids interactions in the gradual accumulation of αS in pathogenic forms and its deposition in Lewy bodies, the pathological hallmark of PD and related synucleinopathies. The peroxisomal biogenesis disorders (PBD), with Zellweger syndrome serving as the prototype of this group, are characterized by malformed and functionally impaired peroxisomes. Here we utilized the PBD mouse models, Pex2-/-, Pex5-/-and Pex13-/-, to study the potential effects of peroxisomal dysfunction on αS-related pathogenesis. We found increased αS oligomerization and phosphorylation and its increased deposition in cytoplasmic inclusions in these PBD mouse models. Further, we show that αS abnormalities correlate with the altered lipid metabolism and specifically, with accumulation of long chain, n-6 polyunsaturated fatty acids, that occurs in the PBD models.

Oxidative stress, mitochondrial and proteostasis malfunction in adrenoleukodystrophy: A paradigm for axonal degeneration

“…Peroxisomes have also been linked to PD [132]. Firsthly, aggregation of α-synuclein in the brain of Pex2 -/-, Pex5 -/-and Pex7 -/-mice was evidenced, and Lewylike inclusions were formed when α-synuclein thereby was overexpressed in Pex5 -/-fibroblasts [166]. Further, reduced catalase activity was reported in the brains of A53T…”

The peroxisome: an update on mysteries

“…Thus, peroxisomes may represent an interesting target to mitigate or even stop the progress of Alzheimer-related diseases. With regard to other neurodegenerative disorders, peroxisomes have been recently described as potentially contributing to the etiology of Parkinsons' disease: Elevated levels of oligomerized and phosphorylated a-synuclein-eventually deposited in Lewy bodies-have been described in mouse models of peroxisome biogenesis disorders (Yakunin et al 2010). Peroxisomes house the enzymes D-amino acid oxidase and D-aspartate oxidase, which degrade D-serine and D-aspartate found in considerable concentrations in the brain.…”

Peroxisomes take shape

“…8). Interestingly, mutations in three different PEX genes have recently been found to underlie late-onset or slowly progressing neurological disorders 21–24 , and similar α-synuclein toxicity and lipid metabolism defects have been found in both Parkinson’s disease and PBDs 25 . Moreover, a correlation has been made between the level of peroxisome proliferation in hippocampal neurons and the protection from β-amyloid neurodegeneration, a process that is linked to Alzheimer’s disease 26 .…”

“…Considering the implications of peroxisomes in neuronal pathologies 25,108 , peroxisome positioning is likely to have additional importance in specific cell types such as neurons, which are extremely long. In mammalian cells, movement along microtubules disperses peroxisomes after fission 89 , and in yeast, peroxisome motility is necessary for inheritance or directed movement of peroxisomes from mother to daughter during cell division, which is paired with the retention of peroxisomes in both cells to ensure equitable distribution of peroxisomes between them.…”