Human recombinant NACP/α-synuclein is aggregated and fibrillated in vitro: Relevance for Lewy body disease

Hashimoto, Makoto; Hsu, Leigh J.; Sisk, Abbyann; Xia, Yu; Takeda, Ayako; Sundsmo, Mary; Masliah, Eliezer

doi:10.1016/s0006-8993(98)00514-9

Cited by 258 publications

(202 citation statements)

References 25 publications

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“…A reasonable hypothesis is that protein insolubility leads to neuronal damage (Conway et al 1998 ;Crowther et al 1998 ;Hashimoto et al 1998). Nonetheless, it remains possible that protein insolubility is merely an epiphenomenon and that the damage to neurons results from soluble factors.…”

Section:         ?mentioning

confidence: 99%

Late‐onset neurodegenerative diseases—the role of protein insolubility

Johnson

2000

Journal of Anatomy

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Recently, mutations of the alpha-synuclein gene were found to cause dominantly inherited Lewy-body Parkinson's disease (PD) and alpha-synuclein was identified as a major component of the Lewy body. However, the cause of the common form of PD, with a multifactorial rather than autosomal dominant inheritance pattern, remains unknown. Alpha-synuclein precipitates slowly and apparently spontaneously at high concentration in solution and the mutations that cause PD accelerate precipitation. Other dominantly inherited late-onset or adult-onset dominantly inherited neurodegenerative diseases are associated with precipitation of proteins. In Alzheimer disease, beta-amyloid and tau abnormalities are present and in prion disorders, prion proteins are found. In Huntington disease, a disorder with expanded CAG repeats, huntingtin precipitates occur. In dominantly inherited spinocerebellar ataxias, also expanded CAG repeat disorders, the corresponding ataxin protein precipitates are found. In multiple system atrophy, alphasynuclein precipitates are encountered and in progressive supranuclear palsy, tau precipitates occur. In familial amyotrophic lateral sclerosis, a group of dominantly inherited disorders, SOD1 precipitates are found. Most of these disorders can involve the basal ganglia in some way.Since similar processes seem to affect neurons of adults or older individuals and since a relatively limited group of proteins seems to be involved, each producing a form of neurodegeneration, it is possible that certain common features are present that affect this group of proteins. Candidates include a conformational shift, as in prions, an abnormality of the ubiquitin-proteosome pathway, as seen in PD, an abnormality of a pathway preventing precipitation (e.g. chaperonins), or potentiation of a pathway promoting precipitation (e.g. gamma-glutamyl-transpeptidase) or apoptosis. Elucidation of the pathways causing this protein insolubilisation is the first step towards approaching prevention and reversal in these late-onset neurodegenerative diseases.

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Section:         ?mentioning

confidence: 99%

Late‐onset neurodegenerative diseases—the role of protein insolubility

Johnson

2000

Journal of Anatomy

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“…[3][4][5] a-Synuclein is capable of selfaggregating to form both oligomers and polymers. [6][7][8] Toxic oligomers form protofibrils that can potentially damage the cell membrane and promote neurodegeneration. 9,10 While in PD a-synuclein accumulation occurs primarily in the striatal nigral system, in DLB a-synuclein also accumulates in the neocortex and hippocampus.…”

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confidence: 99%

An antiaggregation gene therapy strategy for Lewy body disease utilizing β-synuclein lentivirus in a transgenic model

et al. 2004

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Current experimental gene therapy approaches for Parkinson's disease (PD) and dementia with Lewy bodies (DLB) include the use of viral vectors expressing antiapoptosis genes, neurotrophic factors and dopaminergic system enzymes. However, since increasing evidence favors a role for a-synuclein accumulation in the pathogenesis of these disorders, an alternative therapy might require the transfer of genes that might block a-synuclein accumulation. b-Synuclein, the nonamyloidogenic homologue of a-synuclein, has recently been identified as a potential candidate. Thus, in vivo transfer of genes encoding b-synuclein might provide a novel approach to the development of experimental treatments for PD and DLB. To assess this possibility and to better understand the mechanisms involved, a lentiviral vector expressing human (h) b-synuclein (lenti-b-synuclein) was tested in a transgenic (tg) mouse model of ha-synuclein aggregation. This study showed that unilateral intracerebral injection of lenti-b-synuclein reduced the formation of hasynuclein inclusions and the accumulation of ha-synuclein in synapses and ameliorated the neurodegenerative alterations in the tg mice. Both in vivo and in vitro coimmunoprecipitation and immunoblot experiments show that the mechanisms of b-synuclein neuroprotection involve binding of this molecule to ha-synuclein and Akt, resulting in the decreased aggregation and accumulation of ha-synuclein in the synaptic membrane. Together, these data further support a role for b-synuclein in regulating the conformational state of a-synuclein and suggest that this gene transfer approach might have potential for the development of alternative therapies for PD and DLB.

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“…a-Syn is the main protein component of Lewy bodies, 23 but, importantly, the a-syn found in Lewy bodies is misfolded and phosphorylated, 24,25 indicating that a pathogenic variety of a-syn accumulates in diseased or damaged cells. The native a-syn monomer is an unfolded, soluble protein, and in vitro studies have shown that monomeric, oligomeric, and fibrillar species of a-syn exist in equilibrium [26][27][28] (Figure 1a). Upon oligomerization, a-syn remains soluble, but once the protein undergoes fibrillization, a-syn becomes insoluble and has the capacity to selfaggregate.…”

mentioning

confidence: 99%

“…Upon oligomerization, a-syn remains soluble, but once the protein undergoes fibrillization, a-syn becomes insoluble and has the capacity to selfaggregate. [26][27][28] Aggregation of a-syn proteins into b-sheetrich amyloid assembles is a nucleation-dependent process, that is, addition of preformed fibrillar seeds accelerates the process 29 (Figure 1b). Growing evidence suggests that oligomers are the cytotoxic species, although it is unclear if they alone underlie neurotoxicity.…”

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confidence: 99%

A deadly spread: cellular mechanisms of α-synuclein transfer

2011

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Classically, Parkinson's disease (PD) is linked to dopamine neuron death in the substantia nigra pars compacta. Intracytoplasmic protein inclusions named Lewy bodies, and corresponding Lewy neurites found in neuronal processes, are also key features of the degenerative process in the substantia nigra. The molecular mechanisms by which substantia nigra dopamine neurons die and whether the Lewy pathology is directly involved in the cell death pathway are open questions. More recently, it has become apparent that Lewy pathology gradually involves greater parts of the PD brain and is widespread in late stages. In this review, we first discuss the role of misfolded a-synuclein protein, which is the main constituent of Lewy bodies, in the pathogenesis of PD. We then describe recent evidence that a-synuclein might transfer between cells in PD brains. We discuss in detail the possible molecular mechanisms underlying the proposed propagation and the likely consequences for cells that take up a-synuclein. Finally, we focus on aspects of the pathogenic process that could be targeted with new pharmaceutical therapies or used to develop biomarkers for early PD detection. Multiple hypotheses exist to help explain dopamine neuron cell death and Lewy body formation observed in Parkinson's disease (PD). Mutations of the main proteinaceous constituent of Lewy bodies, a-synuclein (a-syn), lead to dominant, familial disease forms. [1][2][3][4][5] More recently, genome-wide association studies (GWASs) identified variants of the a-synuclein gene (SNCA) gene, encoding a-syn protein, that are coupled to increased PD susceptibility, thus clearly linking this protein to idiopathic PD. 6-8 Furthermore, overexpressed and/or misfolded a-syn is pathogenic to cells while a-syn can be secreted from cells, enter other cells, and seed small intracellular aggregates, demonstrating a connection between a-syn and pathogenic mechanisms of PD. [9][10][11][12][13][14][15][16] In parallel, a much-discussed hypothesis by Braak and colleagues 17 states that a pathogenic agent, introduced via ingestion and/or inhalation, may transfer from the entry site along known long, unmyelinated axons to basal brain areas and eventually to brain stem and cortical regions. Although a-syn is unlikely to be this initial pathogen, it might be the initial target of the unknown agent. If a-syn is misfolded because of the action of the unknown agent, it might contribute to the spreading of pathology by moving from one cell to another and triggering misfolding in the recipient cells. If so, it might explain the surprising presence of Lewy bodies in the young neural grafts of transplanted PD patients observed more than a decade after surgery. [18][19][20][21] In this review, we discuss possible mechanisms by which a-syn could spread between cells and have deadly consequences by describing the molecular evidence for a-syn cellular exit, transit to other cells, uptake by cells, intracellular aggregation, and responses to a-syn accumulation.The Relationship Between a-Syn and PD ...

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Human recombinant NACP/α-synuclein is aggregated and fibrillated in vitro: Relevance for Lewy body disease

Cited by 258 publications

References 25 publications

Late‐onset neurodegenerative diseases—the role of protein insolubility

Late‐onset neurodegenerative diseases—the role of protein insolubility

An antiaggregation gene therapy strategy for Lewy body disease utilizing β-synuclein lentivirus in a transgenic model

A deadly spread: cellular mechanisms of α-synuclein transfer

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