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Distinct mechanisms of axonal globule formation in mice expressing human wild type ?-synuclein or dementia with Lewy bodies-linked P123H ?-synuclein.

ABSTRACT: Axonopathy is critical in the early pathogenesis of neurodegenerative diseases, including Parkinson's disease (PD) and dementia with Lewy bodies (DLB). Axonal swellings such as globules and spheroids are a distinct feature of axonopathy and our recent study showed that transgenic (tg) mice expressing DLB-linked P123H ?-synuclein (P123H ?S) were characterized by P123H ?S-immunoreactive axonal swellings (P123H ?S-globules). Therefore, the objectives of this study were to evaluate ?-synuclein (?S)-immunoreactive axonal swellings (?S-globules) in the brains of tg mice expressing human wild-type ?S and to compare them with the globules in P123H ?S tg mice.In ?S tg mice, ?S-globules were formed in an age-dependent manner in various brain regions, including the thalamus and basal ganglia. These globules were composed of autophagosome-like membranous structures and were reminiscent of P123H ?S-globules in P123H ?S tg mice. In the ?S-globules, frequent clustering and deformation of mitochondria were observed. These changes were associated with oxidative stress, based on staining of nitrated ?S and 4-hydroxy-2-nonenal (4-HNE). In accord with the absence of mitochondria in the P123H ?S-globules, staining of nitrated ?S and 4-HNE in these globules was weaker than that for ?S-globules. Leucine-rich repeat kinase 2 (LRRK2), the PARK8 of familial PD, was detected exclusively in ?S-globules, suggesting a specific role of this molecule in these globules.Lysosomal pathology was similarly observed for both ?S- and P123H ?S-globules, while oxidative stress was associated with the ?S-globules, and to a lesser extent with the P123H ?S-globules. Other pathologies, such as mitochondrial alteration and LRRK2 accumulation, were exclusively detected for ?S-globules. Collectively, both ?S- and P123H ?S-globules were formed through similar but distinct pathogenic mechanisms. Our findings suggest that synuclein family members might contribute to diverse axonal pathologies.

SUBMITTER: Sekigawa A

PROVIDER: S-EPMC3546907 | biostudies-other | 2012 Sep

REPOSITORIES: biostudies-other

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Distinct mechanisms of axonal globule formation in mice expressing human wild type α-synuclein or dementia with Lewy bodies-linked P123H β-synuclein.

Sekigawa Akio A Fujita Masayo M Sekiyama Kazunari K Takamatsu Yoshiki Y Hatano Taku T Rockenstein Edward E La Spada Albert R AR Masliah Eliezer E Hashimoto Makoto M

Molecular brain 20120926

<h4>Background</h4>Axonopathy is critical in the early pathogenesis of neurodegenerative diseases, including Parkinson's disease (PD) and dementia with Lewy bodies (DLB). Axonal swellings such as globules and spheroids are a distinct feature of axonopathy and our recent study showed that transgenic (tg) mice expressing DLB-linked P123H β-synuclein (P123H βS) were characterized by P123H βS-immunoreactive axonal swellings (P123H βS-globules). Therefore, the objectives of this study were to evaluat ...[more]

PMID: 23013868

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Project description:Dementia with Lewy bodies is characterized by the accumulation of Lewy bodies and Lewy neurites in the CNS, both of which are composed mainly of aggregated α-synuclein phosphorylated at Ser129. Although phosphorylated α-synuclein is believed to exert toxic effects at the synapse in dementia with Lewy bodies and other α-synucleinopathies, direct evidence for the precise synaptic localization has been difficult to achieve due to the lack of adequate optical microscopic resolution to study human synapses. In the present study we applied array tomography, a microscopy technique that combines ultrathin sectioning of tissue with immunofluorescence allowing precise identification of small structures, to quantitatively investigate the synaptic phosphorylated α-synuclein pathology in dementia with Lewy bodies. We performed array tomography on human brain samples from five patients with dementia with Lewy bodies, five patients with Alzheimer's disease and five healthy control subjects to analyse the presence of phosphorylated α-synuclein immunoreactivity at the synapse and their relationship with synapse size. Main analyses were performed in blocks from cingulate cortex and confirmed in blocks from the striatum of cases with dementia with Lewy bodies. A total of 1 318 700 single pre- or postsynaptic terminals were analysed. We found that phosphorylated α-synuclein is present exclusively in dementia with Lewy bodies cases, where it can be identified in the form of Lewy bodies, Lewy neurites and small aggregates (<0.16 µm3). Between 19% and 25% of phosphorylated α-synuclein deposits were found in presynaptic terminals mainly in the form of small aggregates. Synaptic terminals that co-localized with small aggregates of phosphorylated α-synuclein were significantly larger than those that did not. Finally, a gradient of phosphorylated α-synuclein aggregation in synapses (pre > pre + post > postsynaptic) was observed. These results indicate that phosphorylated α-synuclein is found at the presynaptic terminals of dementia with Lewy bodies cases mainly in the form of small phosphorylated α-synuclein aggregates that are associated with changes in synaptic morphology. Overall, our data support the notion that pathological phosphorylated α-synuclein may disrupt the structure and function of the synapse in dementia with Lewy bodies.

Project description:BackgroundThe objective of this study was to investigate the discriminating value of a range of CSF α-synuclein species for dementia with Lewy bodies compared with Alzheimer's disease, PD, and cognitively normal controls.MethodsWe applied our recently published enzyme-linked immunosorbent assays to measure the CSF levels of total α-synuclein, oligomeric α-synuclein, and phosphorylated α-synuclein in dementia with Lewy bodies (n = 42), Alzheimer's disease (n = 39), PD (n = 46), and controls (n = 78). General linear models corrected for age and sex were performed to assess differences in α-synuclein levels between groups. We used backward-elimination logistic regression analysis to investigate the combined discriminating value of the different CSF α-synuclein species and Alzheimer's disease biomarkers.ResultsCSF levels of total α-synuclein were lower in dementia with Lewy bodies and PD compared with Alzheimer's disease as well as controls (P < 0.001). In contrast, CSF levels of oligomeric α-synuclein were higher in dementia with Lewy bodies and PD compared with Alzheimer's disease (P < 0.05) and controls (P < 0.001). No group differences were found for phosphorylated α-synuclein. In dementia with Lewy bodies and PD, CSF total α-synuclein levels positively correlated with tau and phosphorylated tau (both r > 0.40, P < 0.01), but not with amyloid-β1-42 . The optimal combination to differentiate dementia with Lewy bodies from controls consisted of amyloid-β1-42 , tau, total α-synuclein, oligomeric α-synuclein, age, and sex (AUC, 0.90). To differentiate dementia with Lewy bodies from Alzheimer's disease, the combination of tau and oligomeric α-synuclein resulted in an AUC of 0.83. CSF α-synuclein species do not contribute to the differentiation of dementia with Lewy bodies from PD.ConclusionsCSF α-synuclein species could be useful as part of a biomarker panel for dementia with Lewy bodies. Evaluating both oligomeric α-synuclein and total α-synuclein in CSF helps in the diagnosis of dementia with Lewy bodies. © 2018 The Authors. Movement Disorders published by Wiley Periodicals, Inc. on behalf of International Parkinson and Movement Disorder Society.

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Dataset Information

Distinct mechanisms of axonal globule formation in mice expressing human wild type ?-synuclein or dementia with Lewy bodies-linked P123H ?-synuclein.

Publications

Distinct mechanisms of axonal globule formation in mice expressing human wild type α-synuclein or dementia with Lewy bodies-linked P123H β-synuclein.

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