Publications
Refining α-Synuclein Seed Amplification Assays to Distinguish Parkinson’s Disease from Multiple System Atrophy.
Wiseman, J. A., Turner C.P., Faull, R. L. M., Halliday G., Dieriks, B.V. (2024) Refining α-Synuclein Seed Amplification Assays to Distinguish Parkinson’s Disease from Multiple System Atrophy. Transl. Neurodegener. 14, 7(IF 10.6), 10.1186/s40035-025-00469-6
Background: Parkinson’s disease (PD) and multiple system atrophy (MSA) are two distinct α-synucleinopathies traditionally differentiated through clinical symptoms. Early diagnosis of MSA is problematic, and seed amplification assays (SAAs), such as real-time quaking-induced conversion (RT-QuIC), offer the potential to distinguish these diseases through their underlying α-synuclein (α-Syn) pathology and proteoforms. Currently, SAAs provide a binary result, signifying either the presence or absence of α-Syn seeds. To enhance the diagnostic potential and biological relevance of these assays, there is a pressing need to incorporate quantification and stratification of α-Syn proteoform-specific aggregation kinetics into current SAA pipelines.
Methods: Optimal RT-QuIC assay conditions for α-Syn seeds extracted from PD and MSA patient brains were determined, and assay kinetics were assessed for α-Syn seeds from different pathologically relevant brain regions (medulla, substantia nigra, hippocampus, middle temporal gyrus, and cerebellum). The conformational profiles of diseaseand region-specific α-Syn proteoforms were determined by subjecting the amplified reaction products to concentration-dependent proteolytic digestion with proteinase K.
Results: Using our protocol, PD and MSA could be accurately delineated using proteoform-specific aggregation kinetics, including α-Syn aggregation rate, maximum relative fluorescence, the gradient of amplification, and core protofilament size. MSA cases yielded significantly higher values than PD cases across all four kinetic parameters in brain tissues, with the MSA-cerebellar phenotype having higher maximum relative fluorescence than the MSA-Parkinsonian phenotype. Statistical significance was maintained when the data were analysed regionally and when all regions were grouped.
Conclusions: Our RT-QuIC protocol and analysis pipeline can distinguish between PD and MSA, and between MSA phenotypes. MSA α-Syn seeds induce faster propagation and exhibit higher aggregation kinetics than PD α-Syn, mirroring the biological differences observed in brain tissue. With further validation of these quantitative parameters, we propose that SAAs could advance from a yes/no diagnostic to a theranostic biomarker that could be utilised in developing therapeutics.
Neuronal α-synuclein toxicity is the key driver of neurodegeneration in multiple system atrophy
Wiseman, J. A., Halliday G., Dieriks, B.V. Neuronal α-synuclein toxicity is the key driver of neurodegeneration in multiple system atrophy.Brain awaf030 (IF 11.9) 10.1093/brain/awaf030
Multiple system atrophy (MSA) is a rare, rapidly progressing neurodegenerative disorder often misdiagnosed as Parkinson’s disease (PD). Although both conditions share some clinical features, MSA is distinct in its pathological hallmark: oligodendroglial cytoplasmic α-synuclein (α-Syn) inclusions, known as glial cytoplasmic inclusions. These glial cytoplasmic inclusions are pathognomonic for MSA, but they do not lead to significant oligodendroglial cell loss. Instead, MSA is characterized by a substantially greater loss of non-dopaminergic neurons in the nigrostriatal and olivopontocerebellar systems compared with PD. This widespread neuronal degeneration, which is not seen to the same extent in PD, plays a crucial role in the clinical presentation of MSA and is important to consider if PD is to be redefined as a neuronal α-Syn disease. It also raises the question of differences in the potential toxicity of lesions in MSA and the underlying cause of neuronal death in MSA.
By combining an N-terminus α-Syn antibody that reveals more α-Syn pathology and super-resolution microscopy, we identified α-Syn fibrils in MSA neurons penetrating the nucleus from the cytoplasm, leading to nuclear destruction and neuronal death. Our data indicate an early invasion of neuronal nuclei by α-Syn pathology in MSA, precipitating rapid nuclear envelope destruction, as observed through significant structural damage, including the loss of Lamin integrity. Although the progression of α-Syn pathology from the cytoplasm to the nucleus might be similar in oligodendroglia and neurons, the aggregation state of the α-Syn proteoforms involved differs because proteolytic resistance of α-Syn inclusions is significantly higher in neurons, and the nucleus is destroyed.
We describe the progressive impact of α-Syn nuclear pathology on MSA neurons and show that this is a more detrimental and rapid pathology driving neurodegeneration. Our data suggest that oligodendroglial inclusions contain more soluble, less toxic α-Syn proteoforms, consistent with two distinct α-Syn filaments in MSA. We propose renaming MSA as a neuronal nuclear and oligodendroglial α-synucleinopathy to reflect these two distinct pathologies better.
N-terminus α-synuclein detection reveals new and more diverse aggregate morphologies in multiple system atrophy and Parkinson’s disease.
Wiseman, J. A., Fu Y., Faull, R. L. M., Turner C.P., Curtis M.A., Halliday G., Dieriks, B.V. (2024) N-terminus α-synuclein detection reveals new and more diverse aggregate morphologies in multiple system atrophy and Parkinson’s disease. Transl Neurodegener. 13:67. 10.1186/s40035-024-00456-3 (IF 10.6)
Background: Parkinson’s disease (PD) and multiple system atrophy (MSA) are classified as α-synucleinopathies and are primarily differentiated by their clinical phenotypes. Delineating these diseases based on their specific α-synuclein (α-Syn) proteoform pathologies is crucial for accurate antemortem biomarker diagnosis. Newly identified α-Syn pathologies in PD raise questions about whether MSA exhibits a similar diversity. This prompted the need for a comparative study focusing on α-Syn epitope-specific immunoreactivities in both diseases, which could clarify the extent of pathological overlap and diversity, and guide more accurate biomarker development.
Methods: We utilised a multiplex immunohistochemical approach to detect multiple structural domains of α-Syn proteoforms across multiple regions prone to pathological accumulation in MSA (n = 10) and PD (n = 10). Comparison of epitope-specific α-Syn proteoforms was performed in the MSA medulla, inferior olivary nucleus, substantia nigra, hippocampus, and cerebellum, and in the PD olfactory bulb, medulla, substantia nigra, hippocampus, and entorhinal cortex.
Results: N-terminus and C-terminus antibodies detected significantly more α-Syn pathology in MSA than antibodies for phosphorylated (pS129) α-Syn, which are classically used to detect α-Syn. Importantly, C-terminus immunolabelling is more pronounced in MSA compared to PD. Meanwhile, N-terminus immunolabelling consistently detected the highest percentage of α-Syn across pathologically burdened regions of both diseases, which could be of biological significance. As expected, oligodendroglial involvement distinguished MSA from PD, but in contrast to PD, no substantial astrocytic or microglial α-Syn accumulation in MSA occurred. These data confirm glial-specific changes between these diseases when immunolabelling the N-terminus epitope. In comparison, N-terminus neuronal α-Syn was present in PD and MSA, with most MSA neurons lacking pS129 α-Syn proteoforms. This explains why characterisation of neuronal MSA pathologies is lacking and challenges the reliance on pS129 antibodies for the accurate quantification of α-Syn pathological load across α-synucleinopathies.
Conclusions: These findings underscore the necessity of utilising a multiplex approach to detect α-Syn, most importantly including the N-terminus, to capture the entire spectrum of α-Syn proteoforms in α-synucleinopathies. The data provide novel insights toward the biological differentiation of these α-synucleinopathies and pave the way for more refined antemortem diagnostic methods to facilitate early identification and intervention of these neurodegenerative diseases.
Rethinking ‘Rare’ PINK1 Parkinson’s Disease: A Meta-Analysis of Geographical Prevalence, Phenotypic Diversity, and α-Synuclein Pathology.
Yin, P. E. & Dieriks, B. V. (2025) Rethinking ‘Rare’ PINK1 Parkinson’s Disease: A Meta-Analysis of Geographical Prevalence, Phenotypic Diversity, and α-Synuclein Pathology. J. Park. Dis. 15(1), 10.1177/1877718X241304814 (IF 4)
PTEN-induced kinase 1 (PINK1)-related Parkinson's disease (PD) is traditionally considered a rare autosomal recessive form of early-onset PD (EOPD), lacking classical Lewy body pathology. However, this characterization underestimates and oversimplifies PINK1-PD, largely due to a lack of extensive studies in diverse ethnic populations. This review and meta-analysis explores considerable variations in PINK1 variant rates and the wide heterogeneity influenced by patient- and variant-specific factors, delineating a more precise disease profile. Our findings reveal that PINK1-PD is more common than previously thought, with geographic ‘hotspots’ where up to 9% of EOPD cases are linked to PINK1 variants, including the pathogenic p.Leu347Pro variant affecting 1 in 1300 West Polynesians. Homozygous PINK1-PD typically manifests around age 35, predominantly affecting the lower limbs, with an excellent response to levodopa. Heterozygous PINK1-PD presents an ‘intermediate’ phenotype, with a later onset age (around 43 years) than homozygous PINK1-PD but earlier than idiopathic PD (typically after age 65). The severity of the phenotype is influenced by variant zygosity and pathogenicity, interacting with genetic and environmental factors to push some individuals beyond the disease threshold. Notably, females with PINK1-PD have earlier onset age than males, particularly in homozygous cases and when variants occur in the first half of PINK1's kinase domain. Contrary to traditional views, α-synuclein pathology is present in 87.5% of PINK1-PD postmortem cases across ages and variants. We challenge conventional views on PINK1-PD, highlighting distinct phenotypes influenced by zygosity, sex, and a role for α-synuclein pathology, urging for increased recognition and research of this not-so-rare disease.
From onset to advancement: the temporal spectrum of α-synuclein in synucleinopathies
Wiseman J.A., Reddy K., Dieriks B.V. (2024) From onset to advancement: the temporal spectrum of α-synuclein in synucleinopathies. Ageing Res. Rev. 104, 102640. 10.1016/j.arr.2024.102640 (IF 12.5)
This review provides an in-depth analysis of the complex role of alpha-synuclein (α-Syn) in the development of α-synucleinopathies, with a particular focus on its structural diversity and the resulting clinical variability. The ability of α-Syn to form different strains or polymorphs and undergo various post-translational modifications significantly contributes to the wide range of symptoms observed in disorders such as Parkinson’s disease (PD), dementia with Lewy bodies (DLB), and multiple system atrophy (MSA), as well as in lesser-known non-classical α-synucleinopathies. The interaction between genetic predispositions and environmental factors further complicates α-synucleinopathic disease pathogenesis, influencing the disease-specific onset and progression. Despite their common pathological hallmark of α-Syn accumulation, the clinical presentation and progression of α-synucleinopathies differ significantly, posing challenges for diagnosis and treatment. The intricacies of α-Syn pathology highlight the critical need for a deeper understanding of its biological functions and interactions within the neuronal environment to develop targeted therapeutic strategies. The precise point at which α-Syn aggregation transitions from being a byproduct of initial disease triggers to an active and independent driver of disease progression – through the propagation and acceleration of pathogenic processes – remains unclear. By examining the role of α-Syn across various contexts, we illuminate its dual role as both a marker and a mediator of disease, offering insights that could lead to innovative approaches for managing α-synucleinopathies.
A new seed amplification assay to diagnose multiple system atrophy.
Wiseman, J. A., Halliday G., Dieriks, B.V. (2024) A new seed amplification assay to diagnose multiple system atrophy. Lancet Neurol. 23, 1175–1176 (IF 46.5), 10.1016/S1474-4422(24)00428-9
Parkinson’s disease and multiple system atrophy are both characterised by the pathological accumulation of misfolded α-synuclein protein (thereby, both conditions are referred to as α-synucleinopathies). Compared with Parkinson’s disease, multiple system atrophy is more aggressive, rapidly progressing, and fatal neurodegenerative condition driven by both glial and neuronal pathology.1 Differentiating between Parkinson’s disease and multiple system atrophy is critical for prognosis, treatment response, and survival outcomes.2 However, owing to the overlapping early clinical presentations of α-synucleinopathies, achieving an accurate diagnosis early in the disease course remains highly challenging. Consequently, multiple system atrophy is often misdiagnosed.3
Enhanced detection of distinct honeycomb-structured neuronal SMARCC2 cytobodies in Parkinson’s Disease via Cyclic Heat-Induced Epitope Retrieval (CHIER)
Carmichael-Lowe A., Fleming B., Kreesan R., Wiseman J, Yin E.P., Turner C.P., Faull, RLM, Curtis MA., Dragunow M, Dieriks BV (2024) Enhanced detection of distinct honeycomb-structured neuronal SMARCC2 cytobodies in Parkinson’s Disease via Cyclic Heat-Induced Epitope Retrieval (CHIER). Plos One.19:e0315183.10.1371/journal.pone.0315183
Antigen retrieval is crucial for immunohistochemistry, particularly in formalin-fixed paraffin-embedded brain tissue, where fixation causes extensive crosslinking that masks epitopes. Heat-induced epitope Retrieval (HIER) reverses these crosslinks, improving access to nuclear and aggregated proteins. We introduce Cyclic Heat-Induced Epitope Retrieval (CHIER), an advanced technique that builds on HIER by incorporating repeated cycles of heating and cooling. CHIER optimises antigen retrieval and significantly improves detection. CHIER is particularly effective for detecting chromatin-binding proteins, such as SMARCC2, which are difficult to label using conventional IHC methods. Using CHIER on formalin-fixed paraffin-embedded human brain sections, we achieved robust detection of SMARCC2 in both the nucleus and cytoplasm. CHIER also enhanced the visualisation of large SMARCC2 + cytoplasmic bodies, termed cytobodies, which are increased in Parkinson’s Disease (PD). Our findings suggest that SMARCC2 may translocate from the nucleus to the cytoplasm in PD, potentially implicating SMARCC2 aggregation in the disease’s pathology. Furthermore, CHIER does not negatively impact the antigenicity of other antibodies, supporting its use for multiplex fluorescent immunohistochemistry and super-resolution imaging. These results highlight CHIER’s potential for improving the detection of chromatin-binding and aggregated proteins in neurodegenerative disease research, offering new insights into SMARCC2’s role in Parkinson’s Disease.
Hippocampal protein aggregation signatures fully distinguish pathogenic and wildtype UBQLN2 in amyotrophic lateral sclerosis.
Thumbadoo KM, Dieriks BV, and Swanson MEV,…, Scotter EL (2023). Hippocampal protein aggregation signatures fully distinguish pathogenic and wildtype UBQLN2 in amyotrophic lateral sclerosis. Brain. 2024; 147:3547–61.(IF 11.9), 10.1093/brain/awae140
Pathogenic variants in the UBQLN2 gene cause X-linked dominant amyotrophic lateral sclerosis and/or frontotemporal dementia characterized by ubiquilin 2 aggregates in neurons of the motor cortex, hippocampus and spinal cord. However, ubiquilin 2 neuropathology is also seen in sporadic and familial amyotrophic lateral sclerosis and/or frontotemporal dementia cases not caused by UBQLN2 pathogenic variants, particularly C9orf72-linked cases. This makes the mechanistic role of mutant ubiquilin 2 protein and the value of ubiquilin 2 pathology for predicting genotype unclear. Here we examine a cohort of 44 genotypically diverse amyotrophic lateral sclerosis cases with or without frontotemporal dementia, including eight cases with UBQLN2 variants [resulting in p.S222G, p.P497H, p.P506S, p.T487I (two cases) and p.P497L (three cases)]. Using multiplexed (five-label) fluorescent immunohistochemistry, we mapped the co-localization of ubiquilin 2 with phosphorylated TDP-43, dipeptide repeat aggregates and p62 in the hippocampus of controls (n = 6), or amyotrophic lateral sclerosis with or without frontotemporal dementia in sporadic (n = 20), unknown familial (n = 3), SOD1-linked (n = 1), FUS-linked (n = 1), C9orf72-linked (n = 5) and UBQLN2-linked (n = 8) cases. We differentiate between (i) ubiquilin 2 aggregation together with phosphorylated TDP-43 or dipeptide repeat proteins; and (ii) ubiquilin 2 self-aggregation promoted by UBQLN2 pathogenic variants that cause amyotrophic lateral sclerosis and/or frontotemporal dementia. Overall, we describe a hippocampal protein aggregation signature that fully distinguishes mutant from wild-type ubiquilin 2 in amyotrophic lateral sclerosis with or without frontotemporal dementia, whereby mutant ubiquilin 2 is more prone than wild-type to aggregate independently of driving factors. This neuropathological signature can be used to assess the pathogenicity of UBQLN2 gene variants and to understand the mechanisms of UBQLN2-linked disease.
Aggregate-prone brain regions in Parkinson’s disease are rich in unique N-terminus α-synuclein conformers with high proteolysis susceptibility.
Wiseman JA, Murray HC, Faull RLMF, Dragunow M, Turner CP, Dieriks BV, Curtis, M. A. Aggregate-prone brain regions in Parkinson’s disease are rich in unique N-terminus α-synuclein conformers with high proteolysis susceptibility. Npj Park Dis. 2024;10:1–18 10.1038/s41531-023-00614-w.
In Parkinson’s disease (PD), and other α-synucleinopathies, α-synuclein (α-Syn) aggregates form a myriad of conformational and truncational variants. Most antibodies used to detect and quantify α-Syn in the human brain target epitopes within the C-terminus (residues 96–140) of the 140 amino acid protein and may fail to capture the diversity of α-Syn variants present in PD. We sought to investigate the heterogeneity of α-Syn conformations and aggregation states in the PD human brain by labelling with multiple antibodies that detect epitopes along the entire length of α-Syn. We used multiplex immunohistochemistry to simultaneously immunolabel tissue sections with antibodies mapping the three structural domains of α-Syn. Discrete epitope-specific immunoreactivities were visualised and quantified in the olfactory bulb, medulla, substantia nigra, hippocampus, entorhinal cortex, middle temporal gyrus, and middle frontal gyrus of ten PD cases, and the middle temporal gyrus of 23 PD, and 24 neurologically normal cases. Distinct Lewy neurite and Lewy body aggregate morphologies were detected across all interrogated regions/cases. Lewy neurites were the most prominent in the olfactory bulb and hippocampus, while the substantia nigra, medulla and cortical regions showed a mixture of Lewy neurites and Lewy bodies. Importantly, unique N-terminus immunoreactivity revealed previously uncharacterised populations of (1) perinuclear, (2) glial (microglial and astrocytic), and (3) neuronal lysosomal α-Syn aggregates. These epitope-specific N-terminus immunoreactive aggregate populations were susceptible to proteolysis via time-dependent proteinase K digestion, suggesting a less stable oligomeric aggregation state. Our identification of unique N-terminus immunoreactive α-Syn aggregates adds to the emerging paradigm that α-Syn pathology is more abundant and complex in human brains with PD than previously realised. Our findings highlight that labelling multiple regions of the α-Syn protein is necessary to investigate the full spectrum of α-Syn pathology and prompt further investigation into the functional role of these N-terminus polymorphs.
Wrapping up the role of pericytes in Parkinson’s disease
Stevenson T. J. & Dieriks, B. V. (2023) Wrapping up the role of pericytes in Parkinson’s disease. Neural Regeneration Research 18(11): 2395-2396 doi:10.4103/1673‐5374.371362
Pericytes are classically defined as contractile cells within the central nervous system that regulate blood flow and permeability of the blood-brain barrier (BBB). This one-sided view is gradually changing, and pericytes are now considered versatile cells that can switch their function in response to different stimuli (Uemura et al., 2020). In addition to their role as gatekeepers of the BBB and maintaining homeostasis of the brain’s microenvironment through adjusting the vascular intraluminal diameter, pericytes are both sensors and initiators of inflammation, allowing communication between the cerebral parenchyma and the peripheral system (Dieriks et al., 2022). Pericytes can react quickly by releasing neurotrophins to promote neuroprotection or by secreting pro-inflammatory cytokines, which can exacerbate brain and BBB damage (Dieriks et al., 2022). BBB disruption, blood vessel alterations, and cerebral blood flow abnormalities are commonly seen in neurodegenerative disorders with loss of pericyte coverage present in Parkinson’s disease (PD) and Alzheimer’s disease (Uemura et al., 2020, Elabi et al., 2021).
Absolute quantification of neuromelanin in formalin-fixed human brains using absorbance spectrophotometry
Chand DA, Scadeng M, Dieriks BV (2023) Absolute quantification of neuromelanin in formalin-fixed human brains using absorbance spectrophotometry. PLOS ONE 18 (7) 18:e0288327. doi: https://doi.org/10.1371/journal.pone.0288327
Parkinson’s disease is characterised by a visual, preferential degeneration of the pigmented neurons in the substantia nigra. These neurons are pigmented by neuromelanin which decreases in Parkinson’s disease. Not much is known about NM as it is difficult to study and quantify, primarily due to its insolubility in most solvents except alkali. Neuromelanin quantification could progress the development of biomarkers for prodromal Parkinson’s disease and provide insights into the presently unclear role of neuromelanin in Parkinson’s disease aetiology. Light microscopy with stereology can visualise pigmented neurons, but it cannot quantify neuromelanin concentrations. Absolute neuromelanin quantification using absorbance spectrophotometry is reported in the literature, but the methodology is dated and only works with fresh-frozen tissue. We have developed a quantification protocol to overcome these issues. The protocol involves breakdown of fixed tissue, dissolving the tissue neuromelanin in sodium hydroxide, and measuring the solution’s 350 nm absorbance. Up to 100 brain samples can be analysed in parallel, using as little as 2 mg of tissue per sample. We used synthetic neuromelanin to construct the calibration curve rather than substantia nigra neuromelanin. Our protocol enzymatically synthesises neuromelanin from dopamine and L-cysteine followed by high-heat ageing. This protocol enables successful lysis of the fixed substantia nigra tissue and quantification in three brains, with neuromelanin concentrations ranging from 0.23–0.55 μg/mg tissue. Quantification was highly reproducible with an interassay coefficient of variation of 6.75% (n = 5). The absorbance spectra and elemental composition of the aged synthetic neuromelanin and substantia nigra neuromelanin show excellent overlap. Our protocol can robustly and reliably measure the absolute concentration of neuromelanin in formalin-fixed substantia nigra tissue. This will enable us to study how different factors affect neuromelanin and provide the basis for further development of Parkinson’s disease biomarkers and further research into neuromelanin’s role in the brain.
Multiple system atrophy: α-Synuclein strains at the neuron-oligodendrocyte crossroad
Reddy K,. Dieriks, B. V. (2022) Multiple system atrophy: α-Synuclein strains at the neuron-oligodendrocyte crossroad Molecular Neurodegeneration doi: 10.1186/s13024-022-00579-z
Parkinson’s disease (PD) is a progressive, neurodegenerative disorder characterised by the abnormal accumulation of α-synuclein (α-syn) aggregates. Central to disease progression is the gradual spread of pathological α-syn. α-syn aggregation is closely linked to progressive neuron loss. As such, clearance of α-syn aggregates may slow the progression of PD and lead to less severe symptoms. Evidence that non-neuronal cells play a role in PD and other synucleinopathies such as Lewy body dementia and multiple system atrophy are increasing. Our previous work has shown that pericytes — vascular mural cells that regulate the blood-brain barrier — contain α-syn aggregates in human PD brains. Here, we demonstrate that pericytes efficiently internalise fibrillar α-syn irrespective of being in a monoculture or mixed neuronal cell culture. Pericytes efficiently break down α-syn aggregates in vitro, with clear differences in the number of α-syn aggregates/cell and average aggregate size when comparing five pure α-syn strains (Fibrils, Ribbons, fibrils65, fibrils91 and fibrils110). Furthermore, pericytes derived from PD brains have a less uniform response than those derived from control brains. Our results highlight the vital role brain vasculature may play in reducing α-syn burden in PD.
Human pericytes can degrade diverse alpha-synuclein aggregates.
Dieriks, B. V., Highet B., Alik A., Bellande T., ..., Faull, R. L. Melki R., Curtis, M. A., Dragunow M. (2022) Human pericytes can degrade diverse alpha-synuclein aggregates. Plos One Vol.17(11), p.e0277658 doi:10.1371/journal.pone.0277658
Parkinson’s disease (PD) is a progressive, neurodegenerative disorder characterised by the abnormal accumulation of α-synuclein (α-syn) aggregates. Central to disease progression is the gradual spread of pathological α-syn. α-syn aggregation is closely linked to progressive neuron loss. As such, clearance of α-syn aggregates may slow the progression of PD and lead to less severe symptoms. Evidence is increasing that non-neuronal cells play a role in PD and other synucleinopathies such as Lewy body dementia and multiple system atrophy. Our previous work has shown that pericytes—vascular mural cells that regulate the blood-brain barrier—contain α-syn aggregates in human PD brains. Here, we demonstrate that pericytes efficiently internalise fibrillar α-syn irrespective of being in a monoculture or mixed neuronal cell culture. Pericytes cleave fibrillar α-syn aggregates (Fibrils, Ribbons, fibrils65, fibrils91 and fibrils110), with cleaved α-syn remaining present for up to 21 days. The number of α-syn aggregates/cell and average aggregate size depends on the type of strain, but differences disappear within 5 five hours of treatment. Our results highlight the role brain vasculature may play in reducing α-syn aggregate burden in PD.
α-synuclein inclusions are abundant in non-neuronal cells in the anterior olfactory nucleus of the Parkinson's disease olfactory bulb.
Stevenson T. J., Murray, H. C., Turner, C., Faull, R. L. M., Dieriks, B. V.* & Curtis, M. A.* (2020). α-synuclein inclusions are abundant in non-neuronal cells in the anterior olfactory nucleus of the Parkinson's disease olfactory bulb. Scientific Reports, 10(1), 1-10. doi: 10.1038/s41598-020-63412-x. (* equally contributed co-last authors).
This paper is part of Scientific Reports' Editor's choice: neurodegenerative diseases' and part of Top 100 in Neuroscience. This collection highlights Scientific Reports most downloaded neuroscience papers published in 2020.
Reduced olfactory function (hyposmia) is one of the most common non-motor symptoms experienced by those living with Parkinson’s disease (PD), however, the underlying pathology of the dysfunction is unclear. Recent evidence indicates that α-synuclein (α-syn) pathology accumulates in the anterior olfactory nucleus of the olfactory bulb years before the motor symptoms are present. It is well established that neuronal cells in the olfactory bulb are affected by α-syn, but the involvement of other non-neuronal cell types is unknown. The occurrence of intracellular α-syn inclusions were quantified in four non-neuronal cell types – microglia, pericytes, astrocytes and oligodendrocytes as well as neurons in the anterior olfactory nucleus of post-mortem human PD olfactory bulbs (n = 11) and normal olfactory bulbs (n = 11). In the anterior olfactory nucleus, α-syn inclusions were confirmed to be intracellular in three of the four non-neuronal cell types, where 7.78% of microglia, 3.14% of pericytes and 1.97% of astrocytes were affected. Neurons containing α-syn inclusions comprised 8.60% of the total neuron population. Oligodendrocytes did not contain α-syn. The data provides evidence that non-neuronal cells in the PD olfactory bulb contain α-syn inclusions, suggesting that they may play an important role in the progression of PD.
α-synuclein transfer through tunneling nanotubes occurs in SH-SY5Y cells and primary brain pericytes from Parkinson's disease patients.
Dieriks, B. V., Park, T. I. -H., Fourie, C., Faull, R. L., Dragunow, M., & Curtis, M. A. (2017). α-synuclein transfer through tunneling nanotubes occurs in SH-SY5Y cells and primary brain pericytes from Parkinson's disease patients. Scientific Reports, 7, 42984. doi: 10.1038/srep42984.
Parkinson’s disease (PD) is characterized by the presence of inclusions known as Lewy bodies, which mainly consist of α-synuclein (α-syn) aggregates. There is growing evidence that α-syn self-propagates in non-neuronal cells, thereby contributing to the progression and spread of PD pathology in the brain. Tunneling nanotubes (TNTs) are long, thin, F-actin-based membranous channels that connect cells and have been proposed to act as conduits for α-syn transfer between cells. SH-SY5Y cells and primary human brain pericytes, derived from postmortem PD brains, frequently form TNTs that allow α-syn transfer and long-distance electrical coupling between cells. Pericytes in situ contain α-syn precipitates like those seen in neurons. Exchange through TNTs was rapid, but dependent on the size of the protein. Proteins were able to spread throughout a network of cells connected by TNTs. Transfer through TNTs was not restricted to α-syn; fluorescent control proteins and labeled membrane were also exchanged through TNTs. Most importantly the formation of TNTs and transfer continued during mitosis. Together, our results provide a detailed description of TNTs in SH-SY5Y cells and human brain PD pericytes, demonstrating their role in α-syn transfer and further emphasize the importance that non-neuronal cells, such as pericytes play in disease progression.