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.     

THIS ARTICLE HAS BEEN RETRACTED: Pathological biochemistry of α‐synucleinopathy

Lewy bodies (LBs) are hallmark lesions in the brains of patients with Parkinson's disease (PD) and dementia with Lewy bodies (DLB). We raised a monoclonal antibody LB509 against purified LBs from the brains of patients with DLB that strongly immuolabled LBs, and found that α‐synuclein is one of the major components of LBs. Thus, the deposition of α‐synuclein, an abundant presynaptic brain protein, as fibrillary aggregates in affected neurons or glial cells, was highlighted as a hallmark lesion of a subset of neurodegenerative disorders, including PD, DLB and multiple system atrophy collectively referred to as synucleinopathies. Importantly, the identification of missense mutations in and multiplication of α‐synuclein gene in some pedigrees of familial PD has strongly implicated α‐synuclein in the pathogenesis of PD and other synucleinopathies. We then examined the specific post‐translational modifications that characterize and underlie the aggregation of α‐synuclein in synucleinopathy brains by mass spectrometry and using a specific antibody, and found that serine 129 of α‐synuclein deposited in synucleinopathy lesions is selectively and extensively phosphorylated. Furthermore we generated transgenic C. elegans overexpressing α‐synuclein in neurons, and found that overexpression of familial PD‐linked mutant form of α‐synuclein impairs functions of dopamine neurons. These findings collectively underscore the importance of deposition of α‐synuclein as well as its phosphorylation in the pathogenesis of α‐synucleinopathies.     

Isopentenyl diphosphate isomerase,a cholesterol synthesizing enzyme,is localized in Lewy bodies

Isopentenyl diphosphate isomerase (IDI) is a cytoplasmic enzyme involved in the biosynthesis of isoprenoids including cholesterols. IDI has two isoforms in humans: IDI1 and IDI2. Since lipids are known to be a component of Lewy bodies (LBs), we investigated the immunohistochemical localization of IDI1 and IDI2 in the brain of patients with LB disease and multiple system atrophy (MSA) and normal control subjects. In normal controls, the cytoplasm of neurons was weakly immunostained with anti‐IDI1 and anti‐IDI2 antibodies throughout the nervous system. In LB disease, brainstem‐type LBs were strongly positive for IDI1 and IDI2, and cortical LBs were unstained or barely immunolabeled. Double immunofluorescence staining revealed co‐localization of phosphorylated α‐synuclein with IDI1 or IDI2. Glial cytoplasmic inclusions in MSA were unstained. Previous studies have shown that levels of cholesterol metabolites are increased in the cerebral cortex of patients with LB disease, and that these metabolites accelerate α‐synuclein aggregation. The present findings suggest that IDI1 and IDI2 may be associated with the production of cholesterol metabolites in neurons, leading to α‐synuclein aggregation during the process of LB formation.     

Glycogen synthase kinase‐3β phosphorylates synphilin‐1 in vitro

α‐Synuclein is known to be a major component of Lewy bodies and glial cytoplasmic inclusions in the brains of patients with α‐synucleinopathies. Synphilin‐1, an α‐synuclein‐associated protein, is also present in these inclusions. However, little is known about the post‐translational modifications of synphilin‐1. In the present study, it is reported that synphilin‐1 is phosphorylated by glycogen synthase kinase‐3βin vitro. It is well known that protein phosphorylation is involved in various physiological phenomena, including signal transduction and protein degradation. Therefore, phosphorylation of synphilin‐1 may play an important role in the function of this protein in the brain.     

Unmyelinated axons are more vulnerable to degeneration than myelinated axons of the cardiac nerve in Parkinson's disease

S. Orimo, T. Uchihara, T. Kanazawa, Y. Itoh, K. Wakabayashi, A. Kakita and H. Takahashi (2011) Neuropathology and Applied Neurobiology 37, 791–802 Unmyelinated axons are more vulnerable to degeneration than myelinated axons of the cardiac nerve in Parkinson's disease Aims: We recently demonstrated accumulation of α‐synuclein aggregates of the cardiac sympathetic nerve in Parkinson's disease (PD) and a possible relationship between degeneration of the cardiac sympathetic nerve and α‐synuclein aggregates. The aim of this study is to determine whether there is a difference in the degenerative process between unmyelinated and myelinated axons of the cardiac nerve. Methods: We immunohistochemically examined cardiac tissues from four pathologically verified PD patients, nine patients with incidental Lewy body disease (ILBD) and five control subjects, using antibodies against neurofilament, myelin basic protein (MBP) and α‐synuclein. First, we counted the number of neurofilament‐immunoreactive axons not surrounded by MBP (unmyelinated axons) and those surrounded by MBP (myelinated axons). Next, we counted the number of unmyelinated and myelinated axons with α‐synuclein aggregates. Results: (i) The percentage of unmyelinated axons in PD (77.5 ± 9.14%) was significantly lower compared to that in control subjects (92.2 ± 2.40%). (ii) The ratio of unmyelinated axons with α‐synuclein aggregates to total axons with α‐synuclein aggregates in ILBD ranged from 94.4 to 100 (98.2 ± 2.18%). Among axons with α‐synuclein aggregates, unmyelinated axons were the overwhelming majority, comprising 98.2%. Conclusion: These findings suggest that in PD unmyelinated axons are more vulnerable to degeneration than myelinated axons of the cardiac nerve, because α‐synuclein aggregates accumulate much more abundantly in unmyelinated axons.     

How does parkinson's disease begin? Perspectives on neuroanatomical pathways,prions, and histology

Parkinson's disease (PD) is a multisystem disorder with involvement of the peripheral nervous system. Misfolding and aggregation of α‐synuclein is central to the pathogenesis of PD, and it has been postulated that the disease may originate in olfactory and gastrointestinal nerve terminals. The prion‐like behavior of α‐synuclein has been convincingly demonstrated in vitro and in animal models of PD. Lewy‐type pathology have been detected in peripheral organs many years prior to PD diagnosis, and 2 independent studies have now suggested that truncal vagotomy may be protective against the disorder. Other lines of evidence are difficult to reconcile with a peripheral onset of PD, most importantly the relative scarcity of post mortem cases with isolated gastrointestinal α‐synuclein pathology without concomitant CNS pathology. This Scientific Perspectives article revisits some important topics with implications for the dual‐hit hypothesis. An account of the neuroanatomical pathways necessary for stereotypical α‐synuclein spreading is presented. Parallels to the existing knowledge on true prion disorders, including Creutzfeld‐Jakob disease, are examined. Finally, the vagotomy studies and the somewhat inconsistent findings in the growing literature on peripheral α‐synuclein pathology are discussed. It is concluded that the dual‐hit hypothesis remains a potential explanation for PD pathogenesis, but several issues need to be resolved before more firm conclusions can be drawn. © 2017 International Parkinson and Movement Disorder Society     

Glucocerebrosidase mutations and synucleinopathies: Toward a model of precision medicine

Glucocerebrosidase is a lysosomal enzyme. The characterization of a direct link between mutations in the gene coding for glucocerebrosidase (GBA1) with the development of Parkinson's disease and dementia with Lewy bodies has heightened interest in this enzyme. Although the mechanisms through which glucocerebrosidase regulates the homeostasis of α‐synuclein remains poorly understood, the identification of reduced glucocerebrosidase activity in the brains of patients with PD and dementia with Lewy bodies has paved the way for the development of novel therapeutic strategies directed at enhancing glucocerebrosidase activity and reducing α‐synuclein burden, thereby slowing down or even preventing neuronal death. Here we reviewed the current literature relating to the mechanisms underlying the cross talk between glucocerebrosidase and α‐synuclein, the GBA1 mutation‐associated clinical phenotypes, and ongoing therapeutic approaches targeting glucocerebrosidase. © 2018 International Parkinson and Movement Disorder Society     

Lewy body‐related α‐synucleinopathy in the spinal cord of cases with incidental Lewy body disease

Incidental Lewy body disease (ILBD) represents the early asymptomatic phase of Lewy body diseases (LBD), including idiopathic Parkinson's disease (PD). Although pathological disturbances in the spinal cord, which connects the brain to the peripheral nervous system, plays an important role, the pathology of ILBD has not been adequately examined. Eighteen ILBD and eight age‐matched LBD cases were enrolled in the present study. LB‐related pathology was immunohistochemically evaluated using anti‐phosphorylated α‐synuclein (pαSyn) antibodies, revealing LB‐related pathology in the spinal cords of 15 (83.3%) of the ILBD cases. Attempts were made to identify the early pattern of pαSyn deposition in the spinal cord by comparing the cervical, thoracic, lumbar and sacral segments in detail. Most pαSyn‐positive structures were distributed in and around the autonomic nuclei of the spinal cord. The intermediolateral nuclei in the thoracic segments (Th/IML) were the most frequently and severely affected region, suggesting that Th/IML are the first structures affected. Furthermore, following analysis of the distribution pattern of the pαSyn‐positive structures, it is suspected that LB‐related pathology progresses toward the caudal vertebrae by involving neurons in the spinal cord that are vulnerable to αSyn. It should be noted that the ILBD cases enrolled in the present study were in an earlier stage than the PD cases enrolled in the previous study, and that the present study provides new, previously undescribed information.     

Lysosomal impairment in Parkinson's disease

Impairment of autophagy‐lysosomal pathways (ALPs) is increasingly regarded as a major pathogenic event in neurodegenerative diseases, including Parkinson's disease (PD). ALP alterations are observed in sporadic PD brains and in toxic and genetic rodent models of PD‐related neurodegeneration. In addition, PD‐linked mutations and post‐translational modifications of α‐synuclein impair its own lysosomal‐mediated degradation, thereby contributing to its accumulation and aggregation. Furthermore, other PD‐related genes, such as leucine‐rich repeat kinase‐2 (LRRK2), parkin, and phosphatase and tensin homolog (PTEN)‐induced putative kinase 1 (PINK1), have been mechanistically linked to alterations in ALPs. Conversely, mutations in lysosomal‐related genes, such as glucocerebrosidase (GBA) and lysosomal type 5 P‐type ATPase (ATP13A2), have been linked to PD. New data offer mechanistic molecular evidence for such a connection, unraveling a causal link between lysosomal impairment, α‐synuclein accumulation, and neurotoxicity. First, PD‐related GBA deficiency/mutations initiate a positive feedback loop in which reduced lysosomal function leads to α‐synuclein accumulation, which, in turn, further decreases lysosomal GBA activity by impairing the trafficking of GBA from the endoplasmic reticulum‐Golgi to lysosomes, leading to neurodegeneration. Second, PD‐related mutations/deficiency in the ATP13A2 gene lead to a general lysosomal impairment characterized by lysosomal membrane instability, impaired lysosomal acidification, decreased processing of lysosomal enzymes, reduced degradation of lysosomal substrates, and diminished clearance of autophagosomes, collectively contributing to α‐synuclein accumulation and cell death. According to these new findings, primary lysosomal defects could potentially account for Lewy body formation and neurodegeneration in PD, laying the groundwork for the prospective development of new neuroprotective/disease‐modifying therapeutic strategies aimed at restoring lysosomal levels and function. © 2013 Movement Disorder Society     

Lysosomal‐associated membrane protein 2 isoforms are differentially affected in early Parkinson's disease

Lysosomes are the primary catabolic compartment for the degradation of intracellular proteins through autophagy. The presence of abnormal intracellular α‐synuclein‐positive aggregates in Parkinson's disease (PD) indicates that the degradative capacity of lysosomes is impaired in PD. Specific dysfunction of chaperone‐mediated autophagy (CMA) in PD is suggested by reductions in the CMA membrane receptor, lysosomal‐associated membrane protein (LAMP) 2A, although whether LAMP2A is the only LAMP2 isoform affected by PD is unknown. Messenger RNA (mRNA) and protein expression of all three LAMP2 isoforms was assessed in brain extracts from regions with and without PD‐related increases in α‐synuclein in autopsy samples from subjects in the early pathological stage of PD (n = 9), compared to age‐ and postmortem delay‐matched controls (n = 10). In the early stages of PD, mRNA expression of all LAMP2 isoforms was not different from controls, with LAMP2B and LAMP2C protein levels also unchanged in PD. The selective loss of LAMP2A protein directly correlated with the increased levels of α‐synuclein and decreased levels of the CMA chaperone heat shock cognate protein 70 in the same PD samples, as well as with the accumulation of cytosolic CMA substrate proteins. Our data show that LAMP2 protein isoforms are differentially affected in the early stages of PD, with LAMP2A selectively reduced in association with increased α‐synuclein, and suggests that dysregulation of CMA‐mediated protein degradation occurs before substantial α‐synuclein aggregation in PD. © 2015 International Parkinson and 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     

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     

Expression of Lewy body protein septin 4 in postmortem brain of Parkinson's disease and control subjects

In Parkinson's disease (PD) neuronal degeneration is associated with abnormal protein aggregation in various forms including Lewy bodies (LBs). A major component of LBs is α‐synuclein; septin 4 (SEPT4), a polymerizing GTP‐binding protein that serves as scaffold for diverse molecules has been found to colocalize with α‐synuclein in LBs. The central role of SEPT4 in the etiopathogenesis of PD has been suggested since SEPT4 also shows a physiological association with α‐synuclein and serves as a substrate for parkin. To this end, we studied the expression of septin 4 and α‐synuclein in postmortem human substantia nigra (SN) and amygdala from patients with PD and healthy controls. Twenty patients (14 men : 6 women, onset 63.0 ± 11.4 years, age 77.3 ± 7.6 years, Hoehn and Yahr 4.05/5) and 9 neurologically healthy controls (4 men/5 women, age at death 80.1 ± 8.6 years) were studied. Sporadic PD cases showed a statistically significant decrease of the fold change (FC) of SNCA (FC = 0.31, P = 0.00001) and SEPT4 (FC = 0.67, P = 0.054) gene expressions in the SN and the amygdala (SNCA: FC = 0.49, P = 0.02; SEPT4: FC = 0.32, P = 0.007) versus healthy controls. However, an increase of both proteins in PD versus control subjects was observed with immunoblotting. The semi‐quantitative protein ratio calculations revealed more than 10‐fold increases for both SEPT4 and α‐synuclein in PD versus control subjects. We present for the first time similar signal expression patterns and parallel accumulation of SEPT4 and α‐synuclein in well‐characterized postmortem PD brain. Considering the heterogeneous etiology of sporadic PD and the variability of individual human samples, SEPT4 accumulation may be regarded as one of the common pathological changes in PD and should therefore be further explored. © 2008 Movement Disorder Society     

Fluorescence and autoradiographic evaluation of tau PET ligand PBB3 to α‐synuclein pathology

Background : The tau PET ligand 2‐((1E,3E)‐4‐(6‐([¹¹C]methylamino)pyridin‐3‐yl)buta‐1,3‐dienyl)benzo[d]thiazol‐6‐ol ([¹¹C]PBB3) binds to a wide range of tau pathology; however, binding property of PBB3 to non‐tau inclusions remains unknown. To clarify whether [¹¹C]PBB3 binds to α‐synuclein pathology, reactivity of PBB3 was assessed by in vitro fluorescence and autoradiographic labeling of brain sections from α‐synucleinopathies patients. Method : Of 10 pure Lewy body disease and 120 multiple system atrophy (MSA) cases in the Mayo Clinic brain bank, we selected 3 Lewy body disease and 4 MSA cases with a range of α‐synuclein severity based on the quantitative analysis of α‐synuclein burden. PBB3 fluorescence labeling, double or single immunostaining for α‐synuclein and phospho‐tau, Prussian blue staining, and in vitro autoradiography with [¹¹C]PBB3 were performed for these selected samples. Results : PBB3 fluorescence labeled various α‐synuclein lesions including Lewy bodies, Lewy neurites, spheroids, glial cytoplasmic inclusions, and neuronal cytoplasmic inclusions. Meanwhile, autoradiographic labeling with [¹¹C]PBB3 at 10 nM demonstrated no significant binding in Lewy body disease cases. In contrast, significant autoradiographic binding of [¹¹C]PBB3 to the striatopallidal fibers was found in 2 MSA cases, which had high densities of glial cytoplasmic inclusions without tau or iron deposits in this region. Conclusions : Given that the maximum concentration of [¹¹C]PBB3 in human PET scans is approximately 10 nM, the present data imply that α‐synuclein pathology in Lewy body disease is undetectable by [¹¹C]PBB3‐PET, whereas those in a subset of MSA cases with high densities of glial cytoplasmic inclusions could be captured by this radioligand. © 2017 International Parkinson and Movement Disorder Society     

Selective expression of α‐synuclein‐immunoreactivity in vesicular acetylcholine transporter‐immunoreactive axons in the guinea pig rectum and human colon

Parkinson's disease is a neurodegenerative disorder characterized by motor and nonmotor impairments, including constipation. The hallmark pathological features of Parkinson's disease are Lewy bodies and neurites, of which aggregated α‐synuclein is a major constituent. Frequently, Lewy pathology is identified in the distal gut of constipated Parkinson's disease patients. The neurons that innervate the distal gut that express α‐synuclein have not been identified. We used multiple‐labeling immunohistochemistry and anterograde tracing to quantify which neurons projecting to the guinea pig rectum and human colon expressed α‐synuclein in their axons. α‐Synuclein‐immunoreactivity was present in 24 ± 0.7% of somatostatin (SOM)‐immunoreactive (IR) varicosities; 20 ± 4.3% of substance P (SP)‐IR varicosities and 9 ± 1.3% vasoactive intestinal polypeptide (VIP)‐IR varicosities in guinea pig rectal myenteric ganglia. However, α‐synuclein‐immunoreactivity was localized in significantly more vesicular acetylcholine transporter (VAChT)‐IR varicosities (88 ± 3%, P < 0.001). Of SOM‐IR, SP‐IR, and VIP‐IR varicosities that lacked VAChT‐immunoreactivity, only 1 ± 0.3%, 0 ± 0.3%, and 0% contained α‐synuclein‐immunoreactivity, respectively. 71 ± 0.8% of VAChT‐IR varicosities in myenteric ganglia of human colon were α‐synuclein‐IR. In guinea pig rectal myenteric ganglia, α‐synuclein‐ and VAChT‐immunoreactivity coexisted in 15 ± 1.4% of biotinamide‐labeled extrinsic varicosities; only 1 ± 0.3% of biotinamide‐labeled extrinsic varicosities contained α‐synuclein‐immunoreactivity without VAChT‐immunoreactivity. α‐Synuclein expression in axons to the distal gut correlates closely with expression of the cholinergic marker, VAChT. This is the first report of cell‐selective α‐synuclein expression in the nervous system. Our results suggest cholinergic neurons in the gut may be vulnerable in Parkinson's disease. J. Comp. Neurol. 521:657–676, 2013. © 2012 Wiley Periodicals, Inc.     

Lysosomes,autophagosomes and Alzheimer pathology in dementia with Lewy body disease

A failure of protein degradation may underpin Lewy body disease (LBD) where α‐synuclein is assimilated into the pathognomic Lewy bodies and Lewy neurites. We investigated histological alterations in lysosomes and autophagosomes in the substantia nigra (SN) and cingulate gyrus (CG) in 34 patients with LBD employing antibodies against phosphorylated α‐synuclein and lysosomal (lysosomal associated membrane proteins 1 and 2 (LAMP‐1 and LAMP‐2), cathepsin D (CTSD)) and autophagosomal (microtubule‐associated protein light chain 3α (LC3A)) proteins. Immunostained sections were qualitatively and semi‐quantitatively assessed for the appearance, distribution and intensity of staining. Four LBD patients had mutations in GBA1. There was significantly less LAMP‐1, LAMP‐2 and CTSD immunostaining in neurons of the SN in LBD cases compared to control cases and marginally less LAMP‐1 in patients with GBA1 mutations compared to those without. Loss of LAMP‐1 and CTSD immunoreactivity correlated with cell loss from the SN. There were no changes in LC3A immunoreactivity in the SN, nor any major changes in the CG, or glial cell activity in the SN and CG, for any of the markers. A proportion of amyloid plaques in both the LBD and control cases was immunoreactive for LAMP‐1 and LAMP‐2, but not CTSD or LC3A proteins. These immunohisochemical features were seen in glial cells, which were negative for amyloid‐β. Alterations in lysosomal structure or function, but not macroautophagy, may underpin the pathogenesis of LBD.     

Oligomeric α‐synuclein and β‐amyloid variants as potential biomarkers for Parkinson's and Alzheimer's diseases

Oligomeric forms of α‐synuclein and β‐amyloid are toxic protein variants that are thought to contribute to the onset and progression of Parkinson's disease (PD) and Alzheimer's disease (AD), respectively. The detection of toxic variants in human cerebrospinal fluid (CSF) and blood has great promise for facilitating early and accurate diagnoses of these devastating diseases. Two hurdles that have impeded the use of these protein variants as biomarkers are the availability of reagents that can bind the different variants and a sensitive assay to detect their very low concentrations. We previously isolated antibody‐based reagents that selectively bind two different oligomeric variants of α‐synuclein and two of β‐amyloid, and developed a phage‐based capture enzyme‐linked immunosorbent assay (ELISA) with subfemtomolar sensitivity to quantify their presence. Here, we used these reagents to show that these oligomeric α‐synuclein variants are preferentially present in PD brain tissue, CSF and serum, and that the oligomeric β‐amyloid variants are preferentially present in AD brain tissue, CSF, and serum. Some AD samples also had α‐synuclein pathology and some PD samples also had β‐amyloid pathology, and, very intriguingly, these PD cases also had a history of dementia. Detection of different oligomeric α‐synuclein and β‐amyloid species is an effective method for identifying tissue, CSF and sera from PD and AD samples, respectively, and samples that also contained early stages of other protein pathologies, indicating their potential value as blood‐based biomarkers for neurodegenerative diseases.     

The usual suspects,dopamine and alpha‐synuclein,conspire to cause neurodegeneration

Parkinson's disease (PD) is primarily a movement disorder driven by the loss of dopamine‐producing neurons in the substantia nigra (SN). Early identification of the oxidative properties of dopamine implicated it as a potential source of oxidative stress in PD, yet few studies have investigated dopamine neurotoxicity in vivo. The discovery of PD‐causing mutations in α‐synuclein and the presence of aggregated α‐synuclein in the hallmark Lewy body pathology of PD revealed another important player. Despite extensive efforts, the precise role of α‐synuclein aggregation in neurodegeneration remains unclear. We recently manipulated both dopamine levels and α‐synuclein expression in aged mice and found that only the combination of these 2 factors caused progressive neurodegeneration of the SN and an associated motor deficit. Dopamine modified α‐synuclein aggregation in the SN, resulting in greater abundance of α‐synuclein oligomers and unique dopamine‐induced oligomeric conformations. Furthermore, disruption of the dopamine‐α‐synuclein interaction rescued dopaminergic neurons from degeneration in transgenic Caenorhabditis elegans models. In this Perspective, we discuss these findings in the context of known α‐synuclein and dopamine biology, review the evidence for α‐synuclein oligomer toxicity and potential mechanisms, and discuss therapeutic implications. © 2019 International Parkinson and Movement Disorder Society     

The contribution of Parkin,PINK1 and DJ‐1 genes to selective neuronal degeneration in Parkinson's disease

Parkinson's disease (PD) is characterised by selective and severe degeneration of the substantia nigra pars compacta and the locus coeruleus (LC), which underlies the most prominent symptoms. Although α‐synuclein accumulation has long been established to play a causal role in the disease, it alone cannot explain the selective degenerative pattern. Recent evidence shows that the selective vulnerability could arise due to the large presence of cytosolic catecholamines and Ca²⁺ ions in the substantia nigra pars compacta and LC specifically that can be aberrantly affected by α‐synuclein accumulation. Moreover, each has its own toxic potential, and disturbance of one can exacerbate the toxic effects of the others. This presents a mechanism unique to these areas that can lead to a vicious degenerative cycle. Interestingly, in familial variants of PD, the exact same brain areas are affected, implying the underlying process is likely the same. However, the exact disease mechanisms of many of these genetic variants remain unclear. Here, we review the effects of the PD‐related genes Parkin, PINK1 and DJ‐1. We establish that these mutant varieties can set in motion the same degenerative process involving α‐synuclein, cytosolic catecholamines and Ca²⁺. Additionally, we show indications that model organisms might not accurately represent all components of this central mechanism, explaining why Parkin, PINK1 and DJ‐1 model organisms often lack a convincing PD‐like phenotype.     

Alpha‐synuclein in peripheral tissues and body fluids as a biomarker for Parkinson's disease – a systematic review

Parkinson's disease (PD) is neuropathologically characterized as an alpha‐synucleinopathy. Alpha‐synuclein‐containing inclusions are stained as Lewy bodies and Lewy neurites in the brain, which are the pathological hallmark of PD. However, alpha‐synuclein‐containing inclusions in PD are not restricted to the central nervous system, but are also found in peripheral tissues. Alpha‐synuclein levels can also be measured in body fluids. The aim of this study was to conduct a systematic review of available evidence to determine the utility of alpha‐synuclein as a peripheral biomarker of PD. We searched PubMed (1948 to 26 May 2013), Embase (1974 to 26 May 2013), the Cochrane Library (up to 26 May 2013), LILACS (up to 26 May 2013) and CINAHL (up to 26 May 2013) for the studies of alpha‐synuclein in peripheral tissues or body fluids in PD. A total of 49 studies fulfilled the search criteria. Peripheral tissues such as colonic mucosa showed a sensitivity of 42–90% and a specificity of 100%; submandibular salivary glands showed sensitivity and specificity of 100%; skin biopsy showed 19% sensitivity and 80% specificity in detecting alpha‐synuclein pathology. CSF alpha‐synuclein had 71–94% sensitivity and 25–53% specificity for distinguishing PD from controls. Plasma alpha‐synuclein had 48–53% sensitivity and 69–85% specificity. Neither plasma nor CSF alpha‐synuclein is presently a reliable marker of PD. This differs from alpha‐synuclein in solid tissue samples of the enteric and autonomic nervous system, which offer some potential as a surrogate marker of brain synucleinopathy.