A comparison of changes in proteasomal subunit expression in the substantia nigra in Parkinson's disease, multiple system atrophy and progressive supranuclear palsy

Bukhatwa, Salma; Zeng, Bai-Yun; Rose, Sarah; Jenner, Peter

doi:10.1016/j.brainres.2010.02.045

Cited by 53 publications

(40 citation statements)

References 44 publications

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“…Genetic and pathological studies suggest a role of proteolytic stress in MSA [5, 20]. The current study provides experimental evidence for possible mechanisms of progressive MSA-like neurodegeneration resulting from enhanced proteolytic stress related to systemic proteasome inhibition and oligodendroglial α-synucleinopathy.…”

Section: Discussionmentioning

confidence: 63%

“…A major role of αSYN in the pathogenesis of MSA has also been suggested by genome-wide association (GWA) studies revealing association of polymorphisms within the αSYN gene (SNCA) with increased MSA risk [1, 35]. Furthermore, recent evidence indicates that dysfunction of the ubiquitin–proteasome system (UPS) is a common pathogenic mechanism in α-synucleinopathies including Parkinson’s disease (PD), dementia with Lewy bodies, and MSA [5]. Specifically, in MSA brain tissue reduced immunoreactivity for the 20S-α subunit of the core proteasome complex has been shown in dopaminergic nigral neurons [5].…”

Section: Introductionmentioning

confidence: 99%

“…Furthermore, recent evidence indicates that dysfunction of the ubiquitin–proteasome system (UPS) is a common pathogenic mechanism in α-synucleinopathies including Parkinson’s disease (PD), dementia with Lewy bodies, and MSA [5]. Specifically, in MSA brain tissue reduced immunoreactivity for the 20S-α subunit of the core proteasome complex has been shown in dopaminergic nigral neurons [5]. The 20S proteasome subunit gene expression has been found to be downregulated in the pons of MSA patients [20].…”

Section: Introductionmentioning

confidence: 99%

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Systemic proteasome inhibition triggers neurodegeneration in a transgenic mouse model expressing human α-synuclein under oligodendrocyte promoter: implications for multiple system atrophy

et al. 2012

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Multiple system atrophy (MSA) is a progressive late onset neurodegenerative a-synucleinopathy with unclear pathogenesis. Recent genetic and pathological studies support a central role of a-synuclein (aSYN) in MSA pathogenesis. Oligodendroglial cytoplasmic inclusions of fibrillar aSYN and dysfunction of the ubiquitinproteasome system are suggestive of proteolytic stress in this disorder. To address the possible pathogenic role of oligodendroglial aSYN accumulation and proteolytic failure in MSA we applied systemic proteasome inhibition (PSI) in transgenic mice with oligodendroglial human aSYN expression and determined the presence of MSAlike neurodegeneration in this model as compared to wildtype mice. PSI induced open field motor disability in transgenic aSYN 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 aSYN mice. In contrast no neurodegeneration was detected in PSI-treated wildtype controls. PSI treatment of transgenic aSYN mice was associated with significant ultrastructural alterations including accumulation of fibrillar human aSYN 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.

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Section: Discussionmentioning

confidence: 63%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Systemic proteasome inhibition triggers neurodegeneration in a transgenic mouse model expressing human α-synuclein under oligodendrocyte promoter: implications for multiple system atrophy

et al. 2012

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“…In addition to the accumulation of ubiquitinated proteins, decreased proteasome function has been reported in the hippocampal, parietal, and temporal lobe regions of post-mortem AD brain tissue, but not in unaffected areas such as occipital lobe and cerebellum [13]. Subsequent studies of HD [14], PD [15–17], ALS [18,19], and prion disease [11] samples have also provided post-mortem evidence of downregulation of proteasome function. Thus, the current thinking in the field is that altered proteostasis plays a key role in the pathogenesis of proteinopathies [20,21].…”

Section: The Ubiquitin Proteasome System (Ups) In Neurodegenerative Dmentioning

confidence: 99%

Targeting the 26S Proteasome To Protect Against Proteotoxic Diseases

Myeku

Duff

2018

Trends in Molecular Medicine

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Aggregates of misfolded proteins can compromise the function of the 26S proteasome complex, leaving neurons susceptible to accelerated and impaired protein homeostasis, thereby contributing to the pathogenesis of neurodegeneration. Strategies aimed at enhancing the function of the 26S proteasome via phosphorylation of key subunit epitopes have been effective in reducing protein aggregates in mouse models of disease. We discuss how phosphodiesterase (PDE) inhibitors and G protein-coupled receptor (GPCR)-targeted drugs might be considered as candidate therapeutics, acting on second messenger signal transduction. The range of candidates might address the need forregion-,cell-,oreven cellular compartment-specific modulation. Given the array of clinical and experimental drugs targeting cAMP/cGMP signaling, we propose that proteasome activators targeting secondary messengers might be exploited as novel agents for the treatment or prevention of some neurodegenerative diseases.

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“…Previous investigations of alpha-synucleinopathies like PD have illuminated the role of UPS dysfunction. [132] Specifically occurring in the substantia nigra, the failure of the UPS correlates with the presence of Lewy bodies seen in PD. [132]…”

Section: Proposed Mechanisms Of Msa Pathogenesismentioning

confidence: 99%

Multiple system atrophy: the application of genetics in understanding etiology

Federoff

Schottlaender²,

Houlden³

et al. 2015

Clin Auton Res

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Classically defined phenotypically by a triad of cerebellar ataxia, parkinsonism and autonomic dysfunction in conjunction with pyramidal signs, multiple system atrophy (MSA) is a rare and progressive neurodegenerative disease affecting an estimated 3-4 per every 100,000 individuals among adults 50-99 years of age. With a pathological hallmark of alpha-synuclein-immunoreactive glial cytoplasmic inclusions (GCIs; Papp-Lantos inclusions), MSA patients exhibit marked neurodegenerative changes in the striatonigral and/or olivopontocerebellar structures of the brain. As a member of the alpha-synucleinopathy family, which is defined by its well-demarcated alpha-synuclein-immunoreactive inclusions and aggregation, MSA’s clinical presentation exhibits several overlapping features with other members including Parkinson’s disease (PD) and dementia with Lewy bodies (DLB). Given the extensive fund of knowledge regarding the genetic etiology of PD revealed within the past several years, a genetic investigation of MSA is warranted. While a current genome wide association (GWA) study is underway for MSA to further clarify the role of associated genetic loci and single nucleotide polymorphisms (SNPs), several cases have presented solid preliminary evidence of a genetic etiology. Naturally, genes and variants manifesting known associations with PD (and other phenotypically similar neurodegenerative disorders), including SNCA and MAPT, have been comprehensively investigated in MSA patient cohorts. More recently variants in COQ2 have been linked to MSA in the Japanese population although this finding awaits replication. Nonetheless, significant positive associations with subsequent independent replication studies have been scarce. With very limited information regarding genetic mutations or alterations in gene dosage as a cause of MSA, the search for novel risk genes, which may be in the form of common variants or rare variants, is the logical nexus for MSA research. We believe that the application of next generation genetic methods to MSA will provide valuable insight into the underlying causes of this disease, and will be central to the identification of etiologic based therapies.

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A comparison of changes in proteasomal subunit expression in the substantia nigra in Parkinson's disease, multiple system atrophy and progressive supranuclear palsy

Cited by 53 publications

References 44 publications

Systemic proteasome inhibition triggers neurodegeneration in a transgenic mouse model expressing human α-synuclein under oligodendrocyte promoter: implications for multiple system atrophy

Systemic proteasome inhibition triggers neurodegeneration in a transgenic mouse model expressing human α-synuclein under oligodendrocyte promoter: implications for multiple system atrophy

Targeting the 26S Proteasome To Protect Against Proteotoxic Diseases

Multiple system atrophy: the application of genetics in understanding etiology

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