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

Fujita M, Sekigawa A, Sekiyama K, Takamatsu Y, Hashimoto M - Int J Mol Sci (2012)

Bottom Line: 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.Alternatively, it is possible that "toxic gain of function" of wild type βS occurs during the pathogenesis of sporadic α-synucleinopathies, since tg mice expressing dementia with Lewy bodies-linked P123H βS 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 βS during the pathogenesis of sporadic α-synucleinopathies.

View Article: PubMed Central - PubMed

Affiliation: Division of Sensory and Motor Systems, Tokyo Metropolitan Institute of Medical Science, 2-1-6 Kamikitazawa Setagaya-ku Tokyo 156-0057, Japan; E-Mails: sekigawa-ak@igakuken.or.jp (A.S.); sekiyama-kz@igakuken.or.jp (K.S.); takamatsu-ys@igakuken.or.jp (Y.T.).

ABSTRACT
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 as in cell free and cell culture systems, which suggests that βS might be a negative regulator of neurodegeneration caused by αS, and that "loss of function" of βS might be involved in progression of α-synucleinopathies. Alternatively, it is possible that "toxic gain of function" of wild type βS occurs during the pathogenesis of sporadic α-synucleinopathies, since tg mice expressing dementia with Lewy bodies-linked P123H βS 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 βS during the pathogenesis of sporadic α-synucleinopathies.

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Related in: MedlinePlus

Schematic hypothesis of a multiple-step mechanism through which βS may stimulate the pathogenesis of sporadic α-synucleinopathies.
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f1-ijms-13-11584: Schematic hypothesis of a multiple-step mechanism through which βS may stimulate the pathogenesis of sporadic α-synucleinopathies.

Mentions: At present, it is unknown whether “toxic gain of function” of wild type βS is indeed the case for the pathogenesis of sporadic α-synucleinopathies. In this regard, we propose a hypothetical multiple-step mechanism (steps I–IV) through which wild type βS might stimulate the axonal pathology of α-synucleinopathies in human brains (Scheme 1). In the initial phase, βS might be accumulated in the presynapse (or distal axon) due to genetic factors, environmental factors, and aging. In particular, given the neuroprotective effect of wild type βS, βS might be upregulated to protect against increasing stresses, such as oxidative stress and chronic inflammation, during the course of aging (step I). Accumulated βS might then gradually undergo posttranslational modifications, such as phosphorylation and glycosylation, particularly in the C-terminal region (step II). As a consequence, a small amount of wild type βS with extensive modifications might adopt altered structures (e.g., toxic oligomers, protofibrils) due to aberrant regulation of the C-terminal region. This step may be regarded as “transformation” of βS from a neuroprotective to a neurodegenerative molecule (step III). Then, wild type βS with an altered structure may sequester αS, further stimulating the process of αS aggregation. Once aggregation of αS starts, amyloidogenesis of αS might proceed even in the absence of βS (step IV). Overall, alteration of βS might be involved in the early stage of the amyloidogenesis of αS, whereby altered βS may interact with αS, resulting in initial seeding of aggregated αS and leading to promotion of αS pathology.


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

Fujita M, Sekigawa A, Sekiyama K, Takamatsu Y, Hashimoto M - Int J Mol Sci (2012)

Schematic hypothesis of a multiple-step mechanism through which βS may stimulate the pathogenesis of sporadic α-synucleinopathies.
© Copyright Policy - open-access
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC3472764&req=5

f1-ijms-13-11584: Schematic hypothesis of a multiple-step mechanism through which βS may stimulate the pathogenesis of sporadic α-synucleinopathies.
Mentions: At present, it is unknown whether “toxic gain of function” of wild type βS is indeed the case for the pathogenesis of sporadic α-synucleinopathies. In this regard, we propose a hypothetical multiple-step mechanism (steps I–IV) through which wild type βS might stimulate the axonal pathology of α-synucleinopathies in human brains (Scheme 1). In the initial phase, βS might be accumulated in the presynapse (or distal axon) due to genetic factors, environmental factors, and aging. In particular, given the neuroprotective effect of wild type βS, βS might be upregulated to protect against increasing stresses, such as oxidative stress and chronic inflammation, during the course of aging (step I). Accumulated βS might then gradually undergo posttranslational modifications, such as phosphorylation and glycosylation, particularly in the C-terminal region (step II). As a consequence, a small amount of wild type βS with extensive modifications might adopt altered structures (e.g., toxic oligomers, protofibrils) due to aberrant regulation of the C-terminal region. This step may be regarded as “transformation” of βS from a neuroprotective to a neurodegenerative molecule (step III). Then, wild type βS with an altered structure may sequester αS, further stimulating the process of αS aggregation. Once aggregation of αS starts, amyloidogenesis of αS might proceed even in the absence of βS (step IV). Overall, alteration of βS might be involved in the early stage of the amyloidogenesis of αS, whereby altered βS may interact with αS, resulting in initial seeding of aggregated αS and leading to promotion of αS pathology.

Bottom Line: 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.Alternatively, it is possible that "toxic gain of function" of wild type βS occurs during the pathogenesis of sporadic α-synucleinopathies, since tg mice expressing dementia with Lewy bodies-linked P123H βS 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 βS during the pathogenesis of sporadic α-synucleinopathies.

View Article: PubMed Central - PubMed

Affiliation: Division of Sensory and Motor Systems, Tokyo Metropolitan Institute of Medical Science, 2-1-6 Kamikitazawa Setagaya-ku Tokyo 156-0057, Japan; E-Mails: sekigawa-ak@igakuken.or.jp (A.S.); sekiyama-kz@igakuken.or.jp (K.S.); takamatsu-ys@igakuken.or.jp (Y.T.).

ABSTRACT
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 as in cell free and cell culture systems, which suggests that βS might be a negative regulator of neurodegeneration caused by αS, and that "loss of function" of βS might be involved in progression of α-synucleinopathies. Alternatively, it is possible that "toxic gain of function" of wild type βS occurs during the pathogenesis of sporadic α-synucleinopathies, since tg mice expressing dementia with Lewy bodies-linked P123H βS 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 βS during the pathogenesis of sporadic α-synucleinopathies.

Show MeSH
Related in: MedlinePlus