A comparison of changes in proteasomal subunit expression in the substantia nigra in Parkinson's disease, multiple system atrophy and progressive supranuclear palsy.
ABSTRACT Dysfunction of the ubiquitin-proteasome system (UPS) occurs in dopaminergic neurones in the SN in PD and it is associated with Lewy body formation. However, it remains unknown whether this is specific to PD or whether it also occurs in multiple system atrophy (MSA) and progressive supranuclear palsy (PSP) where nigral dopaminergic neurones also degenerate. In the present study, we investigated changes in the expression of proteasomal subunits in the SN in PD, MSA and PSP. Immunohistochemistry double staining showed that proteasome 20S-alpha4 and -alpha6, and 20S-beta3 and -beta5i subunits are colocalized with tyrosine hydroxylase (TH)-positive cells in the SN of control, PD, MSA and PSP brain. Semi-quantitative analysis showed a significant loss of 20S-alpha4 and -alpha6 subunits TH-positive cells in PD, MSA and PSP compared to control tissue. There was no change in the expression of 20S-beta3 and -beta5i subunits in any of the disease states. The expression of PA700-Rpt5 subunits was not changed in PSP or PD but was significantly increased in MSA compared to control SN. PA700-Rpn10 subunit was not colocalized with TH within dopamine cells but was co-expressed with glial fibrillary acid protein (GFAP) positive astrocytes in the SN of all groups. PA28-alpha immunoreactivity was low in TH positive neurones in control tissue and quantification was not possible. Qualitative analysis suggested a decrease in PD and no immunoreactivity was detected in MSA or PSP. The results show that changes in proteasomal structure occur in the SN in PD, MSA and PSP and that these are similar in nature suggesting that dysfunction of UPS is not specific to PD or to Lewy body formation.
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ABSTRACT: Protein misfolding, aggregation and deposition are common disease mechanisms in many neurodegenerative diseases including Parkinson's disease (PD). Accumulation of damaged or abnormally modified proteins may lead to perturbed cellular function and eventually to cell death. Thus, neurons rely on elaborated pathways of protein quality control and removal to maintain intracellular protein homeostasis. Molecular chaperones, the ubiquitin-proteasome system (UPS) and the autophagy-lysosomal pathway (ALP) are critical pathways that mediate the refolding or removal of abnormal proteins. The successive failure of these protein degradation pathways, as a cause or consequence of early pathological alterations in vulnerable neurons at risk, may present a key step in the pathological cascade that leads to spreading neurodegeneration. A growing number of studies in disease models and patients have implicated dysfunction of the UPS and ALP in the pathogenesis of Parkinson's disease and related disorders. Deciphering the exact mechanism by which the different proteolytic systems contribute to the elimination of pathogenic proteins, like α-synuclein, is therefore of paramount importance. We herein review the role of protein degradation pathways in Parkinson's disease and elaborate on the different contributions of the UPS and the ALP to the clearance of altered proteins. We examine the interplay between different degradation pathways and provide a model for the role of the UPS and ALP in the evolution and progression of α-synuclein pathology. With regards to exciting recent studies we also discuss the putative potential of using protein degradation pathways as novel therapeutic targets in Parkinson's disease.Acta Neuropathologica 06/2012; 124(2):153-72. · 9.32 Impact Factor
Article: Systemic proteasome inhibition triggers neurodegeneration in a transgenic mouse model expressing human α-synuclein under oligodendrocyte promoter: implications for multiple system atrophy.[show abstract] [hide abstract]
ABSTRACT: Multiple system atrophy (MSA) is a progressive late onset neurodegenerative α-synucleinopathy with unclear pathogenesis. Recent genetic and pathological studies support a central role of α-synuclein (αSYN) in MSA pathogenesis. Oligodendroglial cytoplasmic inclusions of fibrillar αSYN and dysfunction of the ubiquitin-proteasome system are suggestive of proteolytic stress in this disorder. To address the possible pathogenic role of oligodendroglial αSYN accumulation and proteolytic failure in MSA we applied systemic proteasome inhibition (PSI) in transgenic mice with oligodendroglial human αSYN expression and determined the presence of MSA-like neurodegeneration in this model as compared to wild-type mice. PSI induced open field motor disability in transgenic αSYN mice but not in wild-type mice. The motor phenotype corresponded to progressive and selective neuronal loss in the striatonigral and olivopontocerebellar systems of PSI-treated transgenic αSYN mice. In contrast no neurodegeneration was detected in PSI-treated wild-type controls. PSI treatment of transgenic αSYN mice was associated with significant ultrastructural alterations including accumulation of fibrillar human αSYN in the cytoplasm of oligodendroglia, which resulted in myelin disruption and demyelination characterized by increased g-ratio. The oligodendroglial and myelin pathology was accompanied by axonal degeneration evidenced by signs of mitochondrial stress and dysfunctional axonal transport in the affected neurites. In summary, we provide new evidence supporting a primary role of proteolytic failure and suggesting a neurodegenerative pathomechanism related to disturbed oligodendroglial/myelin trophic support in the pathogenesis of MSA.Acta Neuropathologica 04/2012; 124(1):51-65. · 9.32 Impact Factor