Interaction between misfolded PrP and the ubiquitin-proteasome system in prion-mediated neurodegeneration

Zhu, Lin; Zhao, Deming; Yang, Lifeng

doi:10.1093/abbs/gmt020

Cited by 12 publications

(11 citation statements)

References 85 publications

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“…These data are consistent with the possibility that the ubiquitin-proteasome system is involved in prion pathogenesis but that it may be more disrupted in the nonamyloid disease phenotype. 77,78 …”

Section: Discussionmentioning

confidence: 99%

Proteomics Analysis of Amyloid and Nonamyloid Prion Disease Phenotypes Reveals Both Common and Divergent Mechanisms of Neuropathogenesis

et al. 2014

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Prion diseases are a heterogeneous group of neurodegenerative disorders affecting various mammals including humans. Prion diseases are characterized by a misfolding of the host-encoded prion protein (PrPC) into a pathological isoform termed PrPSc. In wild-type mice, PrPC is attached to the plasma membrane by a glycosylphosphatidylinositol (GPI) anchor and PrPSc typically accumulates in diffuse nonamyloid deposits with gray matter spongiosis. By contrast, when mice lacking the GPI anchor are infected with the same prion inoculum, PrPSc accumulates in dense perivascular amyloid plaques with little or no gray matter spongiosis. In order to evaluate whether different host biochemical pathways were implicated in these two phenotypically distinct prion disease models, we utilized a proteomics approach. In both models, infected mice displayed evidence of a neuroinflammatory response and complement activation. Proteins involved in cell death and calcium homeostasis were also identified in both phenotypes. However, mitochondrial pathways of apoptosis were implicated only in the nonamyloid form, whereas metal binding and synaptic vesicle transport were more disrupted in the amyloid phenotype. Thus, following infection with a single prion strain, PrPC anchoring to the plasma membrane correlated not only with the type of PrPSc deposition but also with unique biochemical pathways associated with pathogenesis.

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Section: Discussionmentioning

confidence: 99%

Proteomics Analysis of Amyloid and Nonamyloid Prion Disease Phenotypes Reveals Both Common and Divergent Mechanisms of Neuropathogenesis

et al. 2014

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“…PrP isoforms have been shown to directly inhibit the 26S proteasome [ 109 , 110 , 111 , 112 , 113 ]. In vitro data using purified proteasomes and three different cell lines show that PrP oligomers directly inhibit the 26S proteasome [ 112 ].…”

Section: The Molecular Underpinnings Of Prp Sc mentioning

confidence: 99%

What Is Our Current Understanding of PrPSc-Associated Neurotoxicity and Its Molecular Underpinnings?

Hughes

Halliday

2017

Pathogens

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The prion diseases are a collection of fatal, transmissible neurodegenerative diseases that cause rapid onset dementia and ultimately death. Uniquely, the infectious agent is a misfolded form of the endogenous cellular prion protein, termed PrPSc. Despite the identity of the molecular agent remaining the same, PrPSc can cause a range of diseases with hereditary, spontaneous or iatrogenic aetiologies. However, the link between PrPSc and toxicity is complex, with subclinical cases of prion disease discovered, and prion neurodegeneration without obvious PrPSc deposition. The toxic mechanisms by which PrPSc causes the extensive neuropathology are still poorly understood, although recent advances are beginning to unravel the molecular underpinnings, including oxidative stress, disruption of proteostasis and induction of the unfolded protein response. This review will discuss the diseases caused by PrPSc toxicity, the nature of the toxicity of PrPSc, and our current understanding of the downstream toxic signaling events triggered by the presence of PrPSc.

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“…In the brain, disturbances in either of the two cause the accumulation and aggregation of short-lived and misfolded proteins. In aging neurons, UPS activity has been shown to be decreased (Tydlacka et al, 2008), accordingly, age-related alterations in proteasomal activity are implicated in various neurodegenerative diseases (Tydlacka et al, 2008; Tashiro et al, 2012; Lin et al, 2013; Orre et al, 2013). It remains to be examined in more detail whether and how proteasome levels and activity differ between neurons and glia, which would obviously affect the capacity of cells to maintain proper protein homeostasis.…”

Section: Ups In Glia In Relation To Neurodegenerative Diseasesmentioning

confidence: 99%

The ubiquitin proteasome system in glia and its role in neurodegenerative diseases

Jansen

Reits

Hol

2014

Front. Mol. Neurosci.

105

110

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The ubiquitin proteasome system (UPS) is crucial for intracellular protein homeostasis and for degradation of aberrant and damaged proteins. The accumulation of ubiquitinated proteins is a hallmark of many neurodegenerative diseases, including amyotrophic lateral sclerosis, Alzheimer’s, Parkinson’s, and Huntington’s disease, leading to the hypothesis that proteasomal impairment is contributing to these diseases. So far, most research related to the UPS in neurodegenerative diseases has been focused on neurons, while glial cells have been largely disregarded in this respect. However, glial cells are essential for proper neuronal function and adopt a reactive phenotype in neurodegenerative diseases, thereby contributing to an inflammatory response. This process is called reactive gliosis, which in turn affects UPS function in glial cells. In many neurodegenerative diseases, mostly neurons show accumulation and aggregation of ubiquitinated proteins, suggesting that glial cells may be better equipped to maintain proper protein homeostasis. During an inflammatory reaction, the immunoproteasome is induced in glia, which may contribute to a more efficient degradation of disease-related proteins. Here we review the role of the UPS in glial cells in various neurodegenerative diseases, and we discuss how studying glial cell function might provide essential information in unraveling mechanisms of neurodegenerative diseases.

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Interaction between misfolded PrP and the ubiquitin-proteasome system in prion-mediated neurodegeneration

Cited by 12 publications

References 85 publications

Proteomics Analysis of Amyloid and Nonamyloid Prion Disease Phenotypes Reveals Both Common and Divergent Mechanisms of Neuropathogenesis

Proteomics Analysis of Amyloid and Nonamyloid Prion Disease Phenotypes Reveals Both Common and Divergent Mechanisms of Neuropathogenesis

What Is Our Current Understanding of PrPSc-Associated Neurotoxicity and Its Molecular Underpinnings?

The ubiquitin proteasome system in glia and its role in neurodegenerative diseases

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