α-Synuclein is phosphorylated in synucleinopathy lesions

Fujiwara, Hideo; Hasegawa, Masato; Dohmae, Naoshi; Kawashima, A.; Masliah, Eliezer; Goldberg, Matthew S.; Shen, Jie; Takio, Koji; Iwatsubo, Takeshi

doi:10.1038/ncb748

Cited by 1,825 publications

(1,892 citation statements)

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“…We found no difference in specificity whether we used O/P‐aSyn‐Ab. Although phosphorylation is generally considered a marker of choice to delineate pathological aggregates from normal, native aSyn accumulation 35, using the P‐aSyn‐Ab, Bottner et al . 17 and Visanji et al .…”

Section: Discussionmentioning

confidence: 99%

Detection of alpha‐synuclein conformational variants from gastro‐intestinal biopsy tissue as a potential biomarker for Parkinson's disease

Ruffmann

Bengoa-Vergniory

Poggiolini

et al. 2018

Neuropathology Appl Neurobio

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AimsGastrointestinal (GI) α‐synuclein (aSyn) detection as a potential biomarker of Parkinson's disease (PD) is challenged by conflicting results of recent studies. To increase sensitivity and specificity, we applied three techniques to detect different conformations of aSyn in GI biopsies obtained from a longitudinal, clinically well‐characterized cohort of PD patients and healthy controls (HC).MethodsWith immunohistochemistry (IHC), we used antibodies reactive for total, phosphorylated and oligomeric aSyn; with aSyn proximity ligation assay (AS‐PLA), we targeted oligomeric aSyn species specifically; and with paraffin‐embedded tissue blot (AS‐PET‐blot) we aimed to detect fibrillary, synaptic aSyn.ResultsA total of 163 tissue blocks were collected from 51 PD patients (113 blocks) and 21 HC (50 blocks). In 31 PD patients, biopsies were taken before the PD diagnosis (Prodromal); while in 20 PD patients biopsies were obtained after diagnosis (Manifest). The majority of tissues blocks were from large intestine (62%), followed by small intestine (21%), stomach (10%) and oesophagus (7%). With IHC, four staining patterns were detected (neuritic, ganglionic, epithelial and cellular), while two distinct staining patterns were detected both with AS‐PLA (cellular and diffuse signal) and with AS‐PET‐blot (aSyn‐localized and pericrypt signal). The level of agreement between different techniques was low and no single technique or staining pattern reliably distinguished PD patients (Prodromal or Manifest) from HC.ConclusionsOur study suggests that detection of aSyn conformational variants currently considered pathological is not adequate for the diagnosis or prediction of PD. Future studies utilizing novel ultrasensitive amyloid aggregation assays may increase sensitivity and specificity.

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Section: Discussionmentioning

confidence: 99%

Detection of alpha‐synuclein conformational variants from gastro‐intestinal biopsy tissue as a potential biomarker for Parkinson's disease

Ruffmann

Bengoa-Vergniory

Poggiolini

et al. 2018

Neuropathology Appl Neurobio

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“…Several studies of a-synuclein aggregates extracted from brains affected by rare neurodegenerative diseases related to PD, provide tantalizing evidence that pore-like structures do exist in vivo. Several studies of a-synuclein fibrils from diffuse Lewy body disease (DLBD) reveal pore-like structures that co-purify with a-synuclein fibrils (Spillantini et al 1998a ;Fujiwara et al 2002). The resemblance of these structures to the amyloid pores produced from a-synuclein in vitro (Lashuel et al 2002a) is striking.…”

Section: Testing the Amyloid Pore Hypothesis By Attempting To Disprovmentioning

confidence: 99%

Are amyloid diseases caused by protein aggregates that mimic bacterial pore-forming toxins?

Lashuel

Lansbury

2006

Quart. Rev. Biophys.

380

368

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Abstract. Protein fibrillization is implicated in the pathogenesis of most, if not all, ageassociated neurodegenerative diseases, but the mechanism(s) by which it triggers neuronal death is unknown. Reductionist in vitro studies suggest that the amyloid protofibril may be the toxic species and that it may amplify itself by inhibiting proteasome-dependent protein degradation. Although its pathogenic target has not been identified, the properties of the protofibril suggest that neurons could be killed by unregulated membrane permeabilization, possibly by a type of protofibril referred to here as the ' amyloid pore'. The purpose of this review is to summarize the existing supportive circumstantial evidence and to stimulate further studies designed to test the validity of this hypothesis.

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“…In relation to α ‐synucleinopathies in particular, PP2A catalyzes the dephosphorylation of phospho‐Ser 129 α ‐synuclein, and the methylation state of the PP2A C subunit regulates this activity 13. Accordingly, the finding of decreased PP2A methylation in this study provides a molecular mechanism for the reduced PP2A activity reported in α ‐synucleinopathies 16 and is likely a significant contributor to the hyperphosphorylation of aggregated α ‐synuclein in these disorders 10, 29…”

Section: Discussionmentioning

confidence: 53%

“…Pathologic α ‐synuclein accumulation itself may be an inhibitor of PP2A activity resulting in a vicious cycle exacerbating the hyperphosphorylation and aggregation of pathogenic proteins including α ‐synuclein and tau in Lewy body disease 10, 45. Overexpression of α ‐synuclein, particularly its A53T mutant which causes dominantly inherited PD and dementia, increases intracellular levels of reactive oxygen species in SH‐SY5Y neuroblastoma cells ,46 contributing to oxidative stress‐mediated dysregulation of PP2A 42, 44.…”

Section: Discussionmentioning

confidence: 99%

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Dysregulation of protein phosphatase 2A in parkinson disease and dementia with lewy bodies

Park

Lee

Park

et al. 2016

Ann Clin Transl Neurol

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ObjectiveProtein phosphatase 2A (PP2A) is a heterotrimeric holoenzyme composed of a catalytic C subunit, a structural A subunit, and one of several regulatory B subunits that confer substrate specificity. The assembly and activity of PP2A are regulated by reversible methylation of the C subunit. α‐Synuclein, which aggregates in Parkinson disease (PD) and dementia with Lewy bodies (DLB), is phosphorylated at Ser129, and PP2A containing a B55α subunit is a major phospho‐Ser129 phosphatase. The objective of this study was to investigate PP2A in α‐synucleinopathies.MethodsWe compared the state of PP2A methylation, as well as the expression of its methylating enzyme, leucine carboxyl methyltransferase (LCMT‐1), and demethylating enzyme, protein phosphatase methylesterase (PME‐1), in postmortem brains from PD and DLB cases as well as age‐matched Controls. Immunohistochemical studies and quantitative image analysis were employed.Results LCMT‐1 was significantly reduced in the substantia nigra (SN) and frontal cortex in both PD and DLB. PME‐1, on the other hand, was elevated in the PD SN. In concert with these changes, the ratio of methylated PP2A to demethylated PP2A was markedly decreased in PD and DLB brains in both SN and frontal cortex. No changes in total PP2A or total B55α subunit were detected.InterpretationThese findings support the hypothesis that PP2A dysregulation in α‐synucleinopathies may contribute to the accumulation of hyperphosphorylated α‐synuclein and to the disease process, raising the possibility that pharmacological means to enhance PP2A phosphatase activity may be a useful disease‐modifying therapeutic approach.

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α-Synuclein is phosphorylated in synucleinopathy lesions

Cited by 1,825 publications

References 24 publications

Detection of alpha‐synuclein conformational variants from gastro‐intestinal biopsy tissue as a potential biomarker for Parkinson's disease

Detection of alpha‐synuclein conformational variants from gastro‐intestinal biopsy tissue as a potential biomarker for Parkinson's disease

Are amyloid diseases caused by protein aggregates that mimic bacterial pore-forming toxins?

Dysregulation of protein phosphatase 2A in parkinson disease and dementia with lewy bodies

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