Full length α-synuclein is present in cerebrospinal fluid from Parkinson's disease and normal subjects

Borghi, Roberta; Marchese, Roberta; Negro, Alessandro; Marinelli, Lucio; Forloni, Gianluigi; Zaccheo, D; Abbruzzese, Giovanni; Tabaton, Massimo

doi:10.1016/s0304-3940(00)01153-8

Cited by 347 publications

(272 citation statements)

References 13 publications

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“…To examine the effect of Ub chain length on α-Syn fibril formation, we compared the aggregation propensities of WT and K12 tetraubiquitinated α-Syn. The in vitro fibrillization studies were carried out at a low protein concentration (5 μM), to mimic to the best possible extent the estimated physiological concentration of α-Syn in neurons (∼1 μM) (29). At lower concentrations, α-Syn does not form fibrils readily in vitro.…”

Section: Resultsmentioning

confidence: 99%

Synthetic polyubiquitinated α-Synuclein reveals important insights into the roles of the ubiquitin chain in regulating its pathophysiology

Haj‐Yahya

Fauvet

Herman-Bachinsky

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

139

115

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Ubiquitination regulates, via different modes of modifications, a variety of biological processes, and aberrations in the process have been implicated in the pathogenesis of several neurodegenerative diseases. However, our ability to dissect the pathophysiological relevance of the ubiquitination code has been hampered due to the lack of methods that allow site-specific introduction of ubiquitin (Ub) chains to a specific substrate. Here, we describe chemical and semisynthetic strategies for site-specific incorporation of K48-linked di-or tetra-Ub chains onto the side chain of Lys12 of α-Synuclein (α-Syn). These advances provided unique opportunities to elucidate the role of ubiquitination and Ub chain length in regulating α-Syn stability, aggregation, phosphorylation, and clearance. In addition, we investigated the cross-talk between phosphorylation and ubiquitination, the two most common α-Syn pathological modifications identified within Lewy bodies and Parkinson disease. Our results suggest that α-Syn functions under complex regulatory mechanisms involving cross-talk among different posttranslational modifications. eukaryotes is the covalent attachment of ubiquitin (Ub) to proteins. This reversible modification, which regulates a variety of biological processes, such as protein degradation, trafficking, and DNA damage response (1, 2), involves the attachment of the C terminus of Ub mainly to the side chain of a Lys residue in a protein substrate via an isopeptide linkage. The process is catalyzed by three enzymes that act in concert: the Ub-activating enzyme (E1), the Ub-conjugating enzyme (E2), and the Ub ligase (E3). The reaction is repeated, and a second Ub is attached to an internal Lys in the previously conjugated ubiquitin. Several repeats result in the synthesis of a poly-Ub chain that can be of varying lengths and internal linkages. The presence of seven Lys residues as possible anchoring sites within Ub in addition to the N-terminal amine results in a highly complex landscape of diverse Ub bioconjugates, which accounts for the diversity of the Ub signaling (3).Research in the Ub field, which aims at understanding the ubiquitination system at the molecular level, has been hampered by the difficulties of controlling ubiquitination in the cell and challenges associated with the preparation of specific Ub conjugates in vitro. These limitations have inspired the development of novel synthetic strategies to facilitate site-specific ubiquitination of proteins (4, 5). Recent advancements in the field have enabled the synthesis of relatively large amounts of highly complex Ub conjugates of defined covalent structure and provided novel insights into the structural, biochemical, and functional consequences of protein ubiquitination, along with unique opportunities to elucidate the molecular basis of Ub signaling. For example, monoubiquitinated α-Synuclein (α-Syn) and histone H2B bearing native isopeptide bonds were prepared and used to shed light on the role of monoubiquitination in regulating α-Syn aggregation a...

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Section: Resultsmentioning

confidence: 99%

Synthetic polyubiquitinated α-Synuclein reveals important insights into the roles of the ubiquitin chain in regulating its pathophysiology

Haj‐Yahya

Fauvet

Herman-Bachinsky

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

139

115

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“…By contrast, α-synuclein is a cytosolic protein, enriched at cytosol/membrane interfaces (49). However, α-synuclein has been identified in extracellular fluids in patients with PD and normal subjects (50)(51)(52)(53). Further, extracellular secretion of α-synuclein is increased under conditions of cellular stress (54); and α-synuclein can also be released in a calcium-dependent manner via exosomes (55).…”

Section: What Is the Mechanism Of Prosaas Protection Against α-Synucleinmentioning

confidence: 99%

The neural chaperone proSAAS blocks α-synuclein fibrillation and neurotoxicity

Jarvela

Lam

Helwig

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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Emerging evidence strongly suggests that chaperone proteins are cytoprotective in neurodegenerative proteinopathies involving protein aggregation; for example, in the accumulation of aggregated α-synuclein into the Lewy bodies present in Parkinson’s disease. Of the various chaperones known to be associated with neurodegenerative disease, the small secretory chaperone known as proSAAS (named after four residues in the amino terminal region) has many attractive properties. We show here that proSAAS, widely expressed in neurons throughout the brain, is associated with aggregated synuclein deposits in the substantia nigra of patients with Parkinson’s disease. Recombinant proSAAS potently inhibits the fibrillation of α-synuclein in an in vitro assay; residues 158–180, containing a largely conserved element, are critical to this bioactivity. ProSAAS also exhibits a neuroprotective function; proSAAS-encoding lentivirus blocks α-synuclein-induced cytotoxicity in primary cultures of nigral dopaminergic neurons, and recombinant proSAAS blocks α-synuclein–induced cytotoxicity in SH-SY5Y cells. Four independent proteomics studies have previously identified proSAAS as a potential cerebrospinal fluid biomarker in various neurodegenerative diseases. Coupled with prior work showing that proSAAS blocks β-amyloid aggregation into fibrils, this study supports the idea that neuronal proSAAS plays an important role in proteostatic processes. ProSAAS thus represents a possible therapeutic target in neurodegenerative disease.

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“…Interestingly, the intravesicular -synuclein has increased aggregation tendency, secretion of both monomeric and aggregated -synuclein is elevated in response to proteasomal and mitochondrial dysfunction . Evidence of -synuclein release from cells is the presence of full length -synuclein in cerebrospinal fluid from Parkinson's disease and normal subjects (Borghi et al, 2000), and in human plasma (El-Agnaf et al, 2003). Several studies demonstrated that extracellular Lewy bodies and -synuclein-immunoreactive nigral aggregates are often surrounded by microglial or inflammatory mediator such as complements (McGeer et al, 1988;Yamada et al, 1992).…”

Section: α-Synucleinmentioning

confidence: 99%

Microglia, major player in the brain inflammation: their roles in the pathogenesis of Parkinson's disease

Kim

Joh²

2006

Exp Mol Med

593

450

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Inflammation, a self-defensive reaction against various pathogenic stimuli, may become harmful self-damaging process. Increasing evidence has linked chronic inflammation to a number of neurodegenerative disorders including Alzheimer's disease (AD), Parkinson's disease (PD), and multiple sclerosis. In the central nervous system, microglia, the resident innate immune cells play major role in the inflammatory process. Although they form the first line of defense for the neural parenchyma, uncontrolled activation of microglia may directly toxic to neurons by releasing various substances such as inflammatory cytokines (IL-1β, TNF-α, IL-6), NO, PGE2, and superoxide. Moreover, our recent study demonstrated that activated microglia phagocytose not only damaged cell debris but also neighboring intact cells. It further supports their active participation in self-perpetuating neuronal damaging cycles. In the following review, we discuss microglial responses to damaging neurons, known activators released from injured neurons and how microglia cause neuronal degeneration. In the last part, microglial activation and their role in PD are discussed in depth.

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Full length α-synuclein is present in cerebrospinal fluid from Parkinson's disease and normal subjects

Cited by 347 publications

References 13 publications

Synthetic polyubiquitinated α-Synuclein reveals important insights into the roles of the ubiquitin chain in regulating its pathophysiology

Synthetic polyubiquitinated α-Synuclein reveals important insights into the roles of the ubiquitin chain in regulating its pathophysiology

The neural chaperone proSAAS blocks α-synuclein fibrillation and neurotoxicity

Microglia, major player in the brain inflammation: their roles in the pathogenesis of Parkinson's disease

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