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Possible alterations in ?-Synuclein, the non-amyloidogenic homologue of ?-Synuclein, during progression of sporadic ?-synucleinopathies.

ABSTRACT: ?-Synucleinopathies are neurodegenerative disorders that are characterized by progressive decline of motor and non-motor dysfunctions. ?-Synuclein (?S) has been shown to play a causative role in neurodegeneration, but the pathogenic mechanisms are still unclear. Thus, there are no radical therapies that can halt or reverse the disease's progression. ?-Synuclein (?S), the non-amyloidogenic homologue of ?S, ameliorates the neurodegeneration phenotype of ?S in transgenic (tg) mouse models, as well as in cell free and cell culture systems, which suggests that ?S might be a negative regulator of neurodegeneration caused by ?S, and that "loss of function" of ?S might be involved in progression of ?-synucleinopathies. Alternatively, it is possible that "toxic gain of function" of wild type ?S occurs during the pathogenesis of sporadic ?-synucleinopathies, since tg mice expressing dementia with Lewy bodies-linked P123H ?S develop progressive neurodegeneration phenotypes, such as axonal pathology and dementia. In this short review, we emphasize the aspects of "toxic gain of function" of wild type ?S during the pathogenesis of sporadic ?-synucleinopathies.

SUBMITTER: Fujita M

PROVIDER: S-EPMC3472764 | biostudies-literature | 2012

REPOSITORIES: biostudies-literature

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Possible alterations in β-Synuclein, the non-amyloidogenic homologue of α-Synuclein, during progression of sporadic α-synucleinopathies.

Fujita Masayo M Sekigawa Akio A Sekiyama Kazunari K Takamatsu Yoshiki Y Hashimoto Makoto M

International journal of molecular sciences 20120914 9

α-Synucleinopathies are neurodegenerative disorders that are characterized by progressive decline of motor and non-motor dysfunctions. α-Synuclein (αS) has been shown to play a causative role in neurodegeneration, but the pathogenic mechanisms are still unclear. Thus, there are no radical therapies that can halt or reverse the disease's progression. β-Synuclein (βS), the non-amyloidogenic homologue of αS, ameliorates the neurodegeneration phenotype of αS in transgenic (tg) mouse models, as well ...[more]

PMID: 23109872

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Project description:Parkinson's disease (PD) is a progressive neurodegenerative disorder that is neuropathologically characterized by degeneration of dopaminergic neurons of the substantia nigra (SN) and formation of Lewy bodies and Lewy neurites composed of aggregated α-synuclein. Proteolysis of α-synuclein by matrix metalloproteinases was shown to facilitate its aggregation and to affect cell viability. One of the proteolysed fragments, Gln79-α-synuclein, possesses a glutamine residue at its N-terminus. We argue that glutaminyl cyclase (QC) may catalyze the pyroglutamate (pGlu)79-α-synuclein formation and, thereby, contribute to enhanced aggregation and compromised degradation of α-synuclein in human synucleinopathies. Here, the kinetic characteristics of Gln79-α-synuclein conversion into the pGlu-form by QC are shown using enzymatic assays and mass spectrometry. Thioflavin T assays and electron microscopy demonstrated a decreased potential of pGlu79-α-synuclein to form fibrils. However, size exclusion chromatography and cell viability assays revealed an increased propensity of pGlu79-α-synuclein to form oligomeric aggregates with high neurotoxicity. In brains of wild-type mice, QC and α-synuclein were co-expressed by dopaminergic SN neurons. Using a specific antibody against the pGlu-modified neo-epitope of α-synuclein, pGlu79-α-synuclein aggregates were detected in association with QC in brains of two transgenic mouse lines with human α-synuclein overexpression. In human brain samples of PD and dementia with Lewy body subjects, pGlu79-α-synuclein was shown to be present in SN neurons, in a number of Lewy bodies and in dystrophic neurites. Importantly, there was a spatial co-occurrence of pGlu79-α-synuclein with the enzyme QC in the human SN complex and a defined association of QC with neuropathological structures. We conclude that QC catalyzes the formation of oligomer-prone pGlu79-α-synuclein in human synucleinopathies, which may-in analogy to pGlu-Aβ peptides in Alzheimer's disease-act as a seed for pathogenic protein aggregation.

Dataset Information

Possible alterations in ?-Synuclein, the non-amyloidogenic homologue of ?-Synuclein, during progression of sporadic ?-synucleinopathies.

Publications

Possible alterations in β-Synuclein, the non-amyloidogenic homologue of α-Synuclein, during progression of sporadic α-synucleinopathies.

Similar Datasets

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