Stage‐dependent nigral neuronal loss in incidental Lewy body and Parkinson's disease

To gain a better understanding of the significance of α‐synuclein pathological conditions during disease progression in Parkinson's disease, we investigated whether 1) nigral neuronal loss in incidental Lewy body disease and Parkinson's disease donors is associated with the local burden α‐synuclein pathological conditions during progression of pathological conditions; 2) the burden and distribution of α‐synuclein pathological conditions are related to clinical measures of disease progression. Post‐mortem tissue and medical records of 24 Parkinson's disease patients, 20 incidental Lewy body disease donors, and 12 age‐matched controls were obtained from the Netherlands Brain Bank for morphometric analysis. We observed a 20% decrease in nigral neuronal cell density in incidental Lewy body disease compared with controls. Nigral neuronal loss (12%) was already observed before the appearance α‐synuclein aggregates. The progression from Braak α‐synuclein stage 3 to 4 was associated with a significant decline in neuronal cell density (46%). Nigral neuronal loss increased with later Braak α‐synuclein stages but did not vary across consecutive Braak α‐synuclein stages. We observed a negative correlation between neuronal density and local α‐synuclein burden in the substantia nigra of Parkinson's disease patients (ρ = ?0.54), but no relationship with Hoehn & Yahr stage or disease duration. In conclusion, our findings cast doubt on the pathogenic role of α‐synuclein aggregates in elderly, but do suggest that the severity of neurodegeneration and local burden of α‐synuclein pathological conditions are closely coupled during disease progression in Parkinson's disease. © 2014 International Parkinson and Movement Disorder Society     

Lysosomal trafficking defects link Parkinson's disease with Gaucher's disease

Lysosomal dysfunction has been implicated in multiple diseases, including lysosomal storage disorders such as Gaucher's disease, in which loss‐of‐function mutations in the GBA1 gene encoding the lysosomal hydrolase β‐glucocerebrosidase result in lipid substrate accumulation. In Parkinson's disease, α‐synuclein accumulates in Lewy bodies and neurites contributing to neuronal death. Previous clinical and genetic evidence has demonstrated an important link between Parkinson's and Gaucher's disease, as GBA1 mutations and variants increase the risk of Parkinson's and Parkinson's patients exhibit decreased β‐glucocerebrosidase activity. Using human midbrain neuron cultures, we have found that loss of β‐glucocerebrosidase activity promotes α‐synuclein accumulation and toxicity, whereas α‐synuclein accumulation further contributes to decreased lysosomal β‐glucocerebrosidase activity by disrupting β‐glucocerebrosidase trafficking to lysosomes. Moreover, α‐synuclein accumulation disrupts trafficking of additional lysosomal hydrolases, further contributing to lysosomal dysfunction and neuronal dyshomeostasis. Importantly, promoting β‐glucocerebrosidase activity reduces α‐synuclein accumulation and rescues lysosomal and neuronal dysfunction, suggesting that β‐glucocerebrosidase may be an important therapeutic target for advancing drug discovery in synucleinopathies including Parkinson's disease. © 2016 International Parkinson and Movement Disorder Society.     

Alpha‐synuclein in colonic submucosa in early untreated Parkinson's disease

The diagnosis of Parkinson's disease rests on motor signs of advanced central dopamine deficiency. There is an urgent need for disease biomarkers. Clinicopathological evidence suggests that α‐synuclein aggregation, the pathological signature of Parkinson's disease, can be detected in gastrointestinal tract neurons in Parkinson's disease. We studied whether we could demonstrate α‐synuclein pathology in specimens from unprepped flexible sigmoidoscopy of the distal sigmoid colon in early subjects with Parkinson's disease. We also looked for 3‐nitrotyrosine, a marker of oxidative stress. Ten subjects with early Parkinson's disease not treated with dopaminergic agents (7 men; median age, 58.5 years; median disease duration, 1.5 years) underwent unprepped flexible sigmoidoscopy with biopsy of the distal sigmoid colon. Immunohistochemistry studies for α‐synuclein and 3‐nitrotyrosine were performed on biopsy specimens and control specimens from a tissue repository (23 healthy subjects and 23 subjects with inflammatory bowel disease). Nine of 10 Parkinson's disease samples were adequate for study. All showed staining for α‐synuclein in nerve fibers in colonic submucosa. No control sample showed this pattern. A few showed light α‐synuclein staining in round cells. 3‐Nitrotyrosine staining was seen in 87% of Parkinson's disease cases but was not specific for Parkinson's disease. This study suggests a pattern of α‐synuclein staining in Parkinson's disease that was distinct from healthy subjects and those with inflammatory bowel disease. The absence of this pattern in subjects with inflammatory bowel disease suggests it is not a sequel of inflammation or oxidative stress. 3‐Nitrotyrosine immunostaining was common in all groups studied, suggesting oxidative stress in the colonic submucosa. © 2011 Movement Disorder Society.     

Plasma α‐synuclein in patients with Parkinson's disease with and without treatment

Alpha‐synuclein (α‐syn) is an intracellular protein with a high tendency to aggregation. It is the major component of Lewy bodies and may play a key role in the pathogenesis of Parkinson's disease (PD). α‐Syn is also released by neurons and can be detected in biological fluids, such as plasma. The purpose of this study was to determine whether plasma α‐syn concentrations are elevated in newly diagnosed PD patients before treatment (nontreated PD group, ntPD; n = 53) and to compare them with concentrations in PD patients with at least 1 year of specific treatment (tPD; n = 42) and in healthy controls (n = 60). Plasma α‐syn concentrations in the ntPD and tPD groups were similar and significantly higher than in healthy controls. In conclusion, α‐syn was elevated early in the development of PD and specific PD treatment did not change plasma α‐syn levels. © 2010 Movement Disorder Society     

A new role for α‐synuclein in Parkinson's disease: Alteration of ER–mitochondrial communication

Familial cases of Parkinson's disease (PD) can be associated with overexpression or mutation of α‐synuclein, a synaptic protein reported to be localized mainly in the cytosol and mitochondria. We recently showed that wild‐type α‐synuclein is not present in mitochondria, as previously thought, but rather is located in mitochondrial‐associated endoplasmic reticulum membranes. Remarkably, we also found that PD‐related mutated α‐synuclein results in its reduced association with mitochondria‐associated membranes, coincident with a lower degree of apposition of endoplasmic reticulum with mitochondria and an increase in mitochondrial fragmentation, as compared with wild‐type. This new subcellular localization of α‐synuclein raises fundamental questions regarding the relationship of α‐synuclein to mitochondria‐associated membranes function, in both normal and pathological states. In this article, we attempt to relate aspects of PD pathogenesis to what is known about mitochondria‐associated membranes' behavior and function. We hypothesize that early events occurring in dopaminergic neurons at the level of the mitochondria‐associated membranes could cause long‐term disturbances that lead to PD. © 2015 International Parkinson and Movement Disorder Society     

The cellular pathology of Parkinson's disease

Parkinson's disease (PD) is a common neurodegenerative disorder of unknown cause that occurs in adults. The presence of Lewy bodies (LB) in association with nerve cell loss in the substantia nigra and various other regions of the nervous system is a diagnostic hallmark of the disease. In 1997, a mutation was identified in the α‐synuclein gene in families with autosomal dominant PD. Subsequent immunohistochemical studies have revealed that all of the LB in familial and sporadic PD contain the gene product α‐synuclein: abnormal filaments that constitute LB were clearly recognized by antibodies against α‐synuclein. Moreover, it was shown that the glial cells, both astrocytes and oligodendrocytes, are also affected by α‐synuclein pathology. Recently, a novel protein, synphilin‐1, has been identified that interacts with α‐synuclein. Interestingly, synphilin‐1 immunohistochemistry has demonstrated that this protein is present in the central core of classical (brainstem) LB, which are composed mainly of densely packed vesicular structures. The role of both α‐synuclein and synphilin‐1 in normal conditions has yet to be clarified.     

Value of in vivo α‐synuclein deposits in Parkinson's disease: A systematic review and meta‐analysis

Previous studies that have investigated the potential of in vivo abnormal α‐synuclein deposits as a pathological biomarker for PD included few participants and reported different diagnostic accuracies. Here, we aimed to confirm the diagnostic value of in vivo α‐synuclein deposits in PD through a systematic review and meta‐analysis, with special emphasis on determining the tissue most suitable for examination and assessing whether anti‐native α‐synuclein or anti‐phosphorylated α‐synuclein antibodies should be used. Databases were searched on December 30, 2018. We finally included 41 case‐control studies that examined in vivo tissue samples using anti‐native α‐synuclein or anti‐phosphorylated α‐synuclein antibody in PD patients and controls. Using a univariate random‐effects model, pooled sensitivity and specificity (95% confidence interval) of anti‐native α‐synuclein antibody were 0.54 (0.49‐0.60) and 0.72 (0.68‐0.76) for the gastrointestinal tract and 0.76 (0.60‐0.89) and 0.60 (0.43‐0.74) for the skin. Pooled sensitivity and specificity (95% confidence interval) of anti‐phosphorylated α‐synuclein antibody were 0.43 (0.37‐0.48) and 0.82 (0.78‐0.86) for the gastrointestinal tract, 0.76 (0.69‐0.82) and 1.00 (0.98‐1.00) for the skin, 0.42 (0.26‐0.59) and 0.94 (0.84‐0.99) for the minor salivary glands, and 0.66 (0.51‐0.79) and 0.96 (0.86‐1.00) for the submandibular glands. Although ubiquitous heterogeneity between the included studies should be noted when interpreting our results, our analyses demonstrated the following: (1) in vivo α‐synuclein immunoreactivity has the potential as a pathological biomarker for PD; (2) anti‐phosphorylated α‐synuclein antibody consistently has higher specificity than anti‐native α‐synuclein antibody; and (3) skin biopsy examination using anti‐phosphorylated α‐synuclein antibody has the best diagnostic accuracy, although feasibility remains an important issue. © 2019 International Parkinson and Movement Disorder Society     

The Lewy body in Parkinson's disease: Molecules implicated in the formation and degradation of α‐synuclein aggregates

The histological hallmark of Parkinson's disease (PD) is the presence of fibrillar aggregates called Lewy bodies (LBs). LB formation has been considered to be a marker for neuronal degeneration, because neuronal loss is found in the predilection sites for LBs. To date, more than 70 molecules have been identified in LBs, in which α‐synuclein is a major constituent of LB fibrils. α‐synuclein immunohistochemistry reveals that diffuse cytoplasmic staining develops into pale bodies via compaction, and that LBs arise from the peripheral portion of pale bodies. This α‐synuclein abnormality is found in 10% of pigmented neurons in the substantia nigra and more than 50% of those in the locus ceruleus in PD. Recent studies have suggested that oligomers and protofibrils of α‐synuclein are cytotoxic, and that LBs may represent a cytoprotective mechanism in PD.     

Microglial phagocytosis is enhanced by monomeric alpha-synuclein, not aggregated alpha-synuclein: implications for Parkinson's disease

Gathering evidence has associated activation of microglia with the pathogenesis of numerous neurodegenerative diseases of the central nervous system (CNS) such as Alzheimer's disease and Parkinson's disease. Microglia are the resident macrophages of the CNS whose functions include chemotaxis, phagocytosis, and secretion of a variety of cytokines and proteases. In this study, we examined the possibility that alpha-synuclein (alpha-syn), which is associated with the pathogenesis of Parkinson's disease, may affect the phagocytic function of microglia. We found that extracellular monomeric alpha-syn enhanced microglial phagocytosis in both a dose- and time-dependent manner, but beta- and gamma- syn did not. We also found that the N-terminal and NAC region of alpha-syn, especially the NAC region, might be responsible for the effect of alpha-syn on microglial phagocytosis. In contrast to monomeric alpha-syn, aggregated alpha-syn actually inhibited microglial phagocytosis. The different effects of monomeric and aggregated alpha-syn on phagocytosis might be related to their localization in cells. This study indicates that alpha-syn can modulate the function of microglia and influence inflammatory changes such as those seen in neurodegenerative disorders.     

Tau/α‐synuclein ratio and inflammatory proteins in Parkinson's disease: An exploratory study

Background : No CSF or plasma biomarker has been validated for diagnosis or progression of PD. Objectives : To assess whether the CSF and plasma levels of proteins associated with PD neuropathological inclusions and with neuroinflammation might have value in the diagnosis of PD or in relation to disease severity. Methods : CSF levels of α‐synuclein, amyloid‐ß1‐42, total tau, and threonine‐181 phosphorylated tau, as well as CSF and plasma levels of cytokines (interleukin‐1ß, interleukin‐2, interleukin, interferon‐γ, and tumor necrosis factor α) were studied in 40 PD patients and 40 healthy controls. Plasma levels of cytokines were measured in 51 patients and 26 aditional controls. We also explored the Parkinson's Progression Markers Initiative data set as a replication cohort. Results : CSF levels of α‐synuclein, amyloid‐ß1‐42, and tumor necrosis factor α were lower in patients than in controls, and the total tau/α‐synuclein, phosphorylated tau/α‐synuclein, total tau/amyloid‐ß1‐42+α‐synuclein, and phosphorylated tau/amyloid‐ß1‐42+α‐synuclein ratios were higher in patients. The best area under the curve value was obtained for the phosphorylated tau/α‐synuclein ratio alone (0.86) and also when this was combined with tumor necrosis factor α in CSF (0.91; sensitivity 92.9%, specificity 75% for a cut‐off value of ≤ 0.71). Phosphorylated tau/α‐synuclein and phosphorylated tau/amyloid‐ß1‐42+α‐synuclein were higher in patients than in controls of the Parkinson's Progression Markers Initiative database. Plasma cytokines did not differ between groups, although interleukin‐6 levels were positively correlated with UPDRS‐I, ‐II, and ‐III scores. Conclusions : The CSF phosphorylated tau/α‐synuclein ratio alone, and in combination with tumor necrosis factor α and plasma interleukin‐6 levels, might serve as biomarkers to diagnose PD and monitor its severity. © 2017 International Parkinson and Movement Disorder Society     

FGF20 and Parkinson's disease: No evidence of association or pathogenicity via α‐synuclein expression

Genetic variation in fibroblast growth factor 20 (FGF20) has been associated with risk of Parkinson's disease (PD). Functional evidence suggested the T allele of one SNP, rs12720208 C/T, altered PD risk by increasing FGF20 and α‐synuclein protein levels. Herein we report our association study of FGF20 and PD risk in four patient‐control series (total: 1,262 patients and 1,881 controls), and measurements of FGF20 and α‐synuclein protein levels in brain samples (nine patients). We found no evidence of association between FGF20 variability and PD risk, and no relationship between the rs12720208 genotype, FGF20 and α‐synuclein protein levels. © 2009 Movement Disorder Society     

Phosphorylated α‐synuclein in the retina is a biomarker of Parkinson's disease pathology severity

Background : PD patients often have visual alterations, for example, loss of visual acuity, contrast sensitivity or motion perception, and diminished electroretinogram responses. PD pathology is mainly characterized by the accumulation of pathological α‐synuclein deposits in the brain, but little is known about how synucleinopathy affects the retina. Objective : To study the correlation between α‐synuclein deposits in the retina and brain of autopsied subjects with PD and incidental Lewy body disease. Methods : We evaluated the presence of phosphorylated α‐synuclein in the retina of autopsied subjects with PD (9 subjects), incidental Lewy body disease (4 subjects), and controls (6 subjects) by immunohistochemistry and compared the retinal synucleinopathy with brain disease severity indicators. Results : Whereas controls did not show any phosphorylated α‐synuclein immunoreactivity in their retina, all PD subjects and 3 of 4 incidental Lewy body disease subjects had phosphorylated α‐synuclein deposits in ganglion cell perikarya, dendrites, and axons, some of them resembling brain Lewy bodies and Lewy neurites. The Lewy‐type synucleinopathy density in the retina significantly correlated with Lewy‐type synucleinopathy density in the brain, with the Unified Parkinson's disease pathology stage and with the motor UPDRS. Conclusion : These data suggest that phosphorylated α‐synuclein accumulates in the retina in parallel with that in the brain, including in early stages preceding development of clinical signs of parkinsonism or dementia. Therefore, the retina may provide an in vivo indicator of brain pathology severity, and its detection could help in the diagnosis and monitoring of disease progression. © 2018 International Parkinson and Movement Disorder Society