Subcellular orchestration of alpha-synuclein variants in Parkinson’s disease brains revealed by 3D multicolor STED microscopy

AbstractPost-translational modifications of alpha-synuclein (aSyn), particularly phosphorylation at Serine 129 (Ser129-p) and truncation of its C-terminus (CTT), have been implicated in Parkinson’s disease (PD) pathology. To gain more insight in the relevance of Ser129-p and CTT aSyn under physiological and pathological conditions, we investigated their subcellular distribution patterns in normal aged and PD brains using highly-selective antibodies in combination with 3D multicolor STED microscopy. We show that CTT aSyn localizes in mitochondria in PD patients and controls, whereas the organization of Ser129-p in a cytoplasmic network is strongly associated with pathology. Nigral Lewy bodies show an onion skin-like architecture, with a structured framework of Ser129-p aSyn and neurofilaments encapsulating CTT aSyn in their core, which displayed high content of proteins and lipids by label-free CARS microscopy. The subcellular phenotypes of antibody-labeled pathology identified in this study provide evidence for a crucial role of Ser129-p aSyn in Lewy body formation.

Download Full-text

Cytotoxicity and Mitochondrial Dysregulation Caused by α-Synuclein in Dictyostelium discoideum

Cells ◽

10.3390/cells9102289 ◽

2020 ◽

Vol 9 (10) ◽

pp. 2289 ◽

Cited By ~ 1

Author(s):

Sanjanie Fernando ◽

Claire Y. Allan ◽

Katelyn Mroczek ◽

Xavier Pearce ◽

Oana Sanislav ◽

...

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Dictyostelium Discoideum ◽

Mitochondrial Function ◽

Molecular Mechanisms ◽

Lewy Bodies ◽

Alpha Synuclein ◽

Cell Cortex ◽

Mutant Proteins ◽

C Terminus

Alpha synuclein has been linked to both sporadic and familial forms of Parkinson’s disease (PD) and is the most abundant protein in Lewy bodies a hallmark of Parkinson’s disease. The function of this protein and the molecular mechanisms underlying its toxicity are still unclear, but many studies have suggested that the mechanism of α-synuclein toxicity involves alterations to mitochondrial function. Here we expressed human α-synuclein and two PD-causing α-synuclein mutant proteins (with a point mutation, A53T, and a C-terminal 20 amino acid truncation) in the eukaryotic model Dictyostelium discoideum. Mitochondrial disease has been well studied in D. discoideum and, unlike in mammals, mitochondrial dysfunction results in a clear set of defective phenotypes. These defective phenotypes are caused by the chronic hyperactivation of the cellular energy sensor, AMP-activated protein kinase (AMPK). Expression of α-synuclein wild type and mutant forms was toxic to the cells and mitochondrial function was dysregulated. Some but not all of the defective phenotypes could be rescued by down regulation of AMPK revealing both AMPK-dependent and -independent mechanisms. Importantly, we also show that the C-terminus of α-synuclein is required and sufficient for the localisation of the protein to the cell cortex in D. discoideum.

Download Full-text

A Comprehensive Study of miRNAs in Parkinson’s Disease: Diagnostics and Therapeutic Approaches

CNS & Neurological Disorders - Drug Targets ◽

10.2174/1871527321666220111152756 ◽

2022 ◽

Vol 21 ◽

Author(s):

Saima Owais ◽

Yasir Hasan Siddique

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Lewy Bodies ◽

Alpha Synuclein ◽

Therapeutic Approaches ◽

Molecular Events ◽

Disease Diagnostics ◽

Therapeutic Molecules ◽

Comprehensive Study

Abstract: Parkinson’s disease (PD) is the second most debilitating neurodegenerative movement disorder. It is characterized by the presence of fibrillar alpha-synuclein amassed in the neurons, known as Lewy bodies. Certain cellular and molecular events are involved leading to the degeneration of dopaminergic neurons. However, the origin and implication of such events are still uncertain. Nevertheless, the role of microRNAs (miRNAs) as important biomarkers and therapeutic molecules is unquestionable. The most challenging task by far in PD treatment has been its late diagnosis followed by therapeutics. miRNAs are an emerging hope to meet the need of early diagnosis, thereby promising an improved movement symptom and prolonged life of the patients. The continuous efforts in discovering the role of miRNAs could be made possible by the utilisation of various animal models of PD. These models help us to understand insights into the mechanism of the disease. Moreover, miRNAs have been surfaced as therapeutically important molecules with distinct delivery systems enhancing their success rate. This review aims at providing an outline of different miRNAs implicated in either PD-associated gene regulation or involved in therapeutics.

Download Full-text

The role of natural killer cells in Parkinson’s disease

Experimental & Molecular Medicine ◽

10.1038/s12276-020-00505-7 ◽

2020 ◽

Vol 52 (9) ◽

pp. 1517-1525

Author(s):

Rachael H. Earls ◽

Jae-Kyung Lee

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Natural Killer Cells ◽

Natural Killer ◽

Cell Function ◽

Lewy Bodies ◽

Alpha Synuclein ◽

Primary Component ◽

Killer Cells

Abstract Numerous lines of evidence indicate an association between sustained inflammation and Parkinson’s disease, but whether increased inflammation is a cause or consequence of Parkinson’s disease remains highly contested. Extensive efforts have been made to characterize microglial function in Parkinson’s disease, but the role of peripheral immune cells is less understood. Natural killer cells are innate effector lymphocytes that primarily target and kill malignant cells. Recent scientific discoveries have unveiled numerous novel functions of natural killer cells, such as resolving inflammation, forming immunological memory, and modulating antigen-presenting cell function. Furthermore, natural killer cells are capable of homing to the central nervous system in neurological disorders that exhibit exacerbated inflammation and inhibit hyperactivated microglia. Recently, a study demonstrated that natural killer cells scavenge alpha-synuclein aggregates, the primary component of Lewy bodies, and systemic depletion of natural killer cells results in exacerbated neuropathology in a mouse model of alpha-synucleinopathy, making them a highly relevant cell type in Parkinson’s disease. However, the exact role of natural killer cells in Parkinson’s disease remains elusive. In this review, we introduce the systemic inflammatory process seen in Parkinson’s disease, with a particular focus on the direct and indirect modulatory capacity of natural killer cells in the context of Parkinson’s disease.

Download Full-text

The subcellular arrangement of alpha-synuclein proteoforms in the Parkinson’s disease brain as revealed by multicolor STED microscopy

Acta Neuropathologica ◽

10.1007/s00401-021-02329-9 ◽

2021 ◽

Author(s):

Tim E. Moors ◽

Christina A. Maat ◽

Daniel Niedieker ◽

Daniel Mona ◽

Dennis Petersen ◽

...

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

High Resolution ◽

Physiological Role ◽

Alpha Synuclein ◽

Stimulated Emission ◽

Disease Stage ◽

Post Mortem ◽

Label Free ◽

Sted Microscopy

AbstractVarious post-translationally modified (PTM) proteoforms of alpha-synuclein (aSyn)—including C-terminally truncated (CTT) and Serine 129 phosphorylated (Ser129-p) aSyn—accumulate in Lewy bodies (LBs) in different regions of the Parkinson’s disease (PD) brain. Insight into the distribution of these proteoforms within LBs and subcellular compartments may aid in understanding the orchestration of Lewy pathology in PD. We applied epitope-specific antibodies against CTT and Ser129-p aSyn proteoforms and different aSyn domains in immunohistochemical multiple labelings on post-mortem brain tissue from PD patients and non-neurological, aged controls, which were scanned using high-resolution 3D multicolor confocal and stimulated emission depletion (STED) microscopy. Our multiple labeling setup highlighted a consistent onion skin-type 3D architecture in mature nigral LBs in which an intricate and structured-appearing framework of Ser129-p aSyn and cytoskeletal elements encapsulates a core enriched in CTT aSyn species. By label-free CARS microscopy we found that enrichments of proteins and lipids were mainly localized to the central portion of nigral aSyn-immunopositive (aSyn+) inclusions. Outside LBs, we observed that 122CTT aSyn+ punctae localized at mitochondrial membranes in the cytoplasm of neurons in PD and control brains, suggesting a physiological role for 122CTT aSyn outside of LBs. In contrast, very limited to no Ser129-p aSyn immunoreactivity was observed in brains of non-neurological controls, while the alignment of Ser129-p aSyn in a neuronal cytoplasmic network was characteristic for brains with (incidental) LB disease. Interestingly, Ser129-p aSyn+ network profiles were not only observed in neurons containing LBs but also in neurons without LBs particularly in donors at early disease stage, pointing towards a possible subcellular pathological phenotype preceding LB formation. Together, our high-resolution and 3D multicolor microscopy observations in the post-mortem human brain provide insights into potential mechanisms underlying a regulated LB morphogenesis.

Download Full-text

Does human alpha synuclein behave like prions?

CNS & Neurological Disorders - Drug Targets ◽

10.2174/1871527320666210420140123 ◽

2021 ◽

Vol 20 ◽

Author(s):

Yasir Hasan Siddique

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Dopaminergic Neurons ◽

Synaptic Vesicles ◽

Lewy Bodies ◽

Alpha Synuclein ◽

Present Review ◽

Exact Role

: Alpha synuclein (α-synuclein) is a protein which is abundantly found in brain and in lesser amount in heart and muscles. The exact role of α-synuclein is not known but it is consider to control the movement of synaptic vesicles. Its overexpression in the neurons leads to the formation of Lewy bodies which specifically damage the dopaminergic neurons in the subtantianigra of the mid brain and leads to the progression of Parkinson’s disease (PD). There are evidences that aggregates of α-synuclein behaves like prions. The present review is an attempt to put forth the nature of α-synuclein as prions.

Download Full-text

Modulation of the Interactions Between α-Synuclein and Lipid Membranes by Post-translational Modifications

Frontiers in Neurology ◽

10.3389/fneur.2021.661117 ◽

2021 ◽

Vol 12 ◽

Author(s):

Rosie Bell ◽

Michele Vendruscolo

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Lipid Membranes ◽

Lewy Bodies ◽

Lewy Neurites ◽

Post Translational Modifications ◽

Therapeutic Tools ◽

Cellular Components ◽

The Impact

Parkinson's disease is characterised by the presence in brain tissue of aberrant inclusions known as Lewy bodies and Lewy neurites, which are deposits composed by α-synuclein and a variety of other cellular components, including in particular lipid membranes. The dysregulation of the balance between lipid homeostasis and α-synuclein homeostasis is therefore likely to be closely involved in the onset and progression of Parkinson's disease and related synucleinopathies. As our understanding of this balance is increasing, we describe recent advances in the characterisation of the role of post-translational modifications in modulating the interactions of α-synuclein with lipid membranes. We then discuss the impact of these advances on the development of novel diagnostic and therapeutic tools for synucleinopathies.

Download Full-text

Faculty Opinions recommendation of The role of ubiquitin linkages on alpha-synuclein induced-toxicity in a Drosophila model of Parkinson's disease.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.13371031.14741147 ◽

2011 ◽

Author(s):

Keith Wilkinson

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Alpha Synuclein ◽

Drosophila Model

Download Full-text

Fibroblast Growth Factor 20 Gene Polymorphism in Parkinson’s Disease in Asian Population: A Meta-Analysis

Genes ◽

10.3390/genes12050674 ◽

2021 ◽

Vol 12 (5) ◽

pp. 674

Author(s):

Han-Lin Chiang ◽

Yih-Ru Wu ◽

Yi-Chun Chen ◽

Hon-Chung Fung ◽

Chiung-Mei Chen

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Meta Analysis ◽

Lewy Bodies ◽

Asian Population ◽

Protective Role ◽

Lewy Neurites ◽

Chinese Populations ◽

Study Results

Parkinson’s disease (PD) is a neurodegenerative disease with the pathological hallmark of Lewy bodies and Lewy neurites composed of α-synuclein. The SNP rs591323 is one of the risk loci located near the FGF20 gene that has been implicated in PD. The variation of FGF20 in the 3′ untranslated region was shown to increase α-synuclein expression. We examined the association of rs591323 with the risk of PD in a Taiwanese population and conducted a meta-analysis, including our study and two other studies from China, to further confirm the role of this SNP in Taiwanese/Chinese populations. A total of 586 patients with PD and 586 health controls (HCs) were included in our study. We found that the minor allele (A) and the AA + GA genotype under the dominant model are significantly less frequent in PD than in controls. The meta-analysis consisted of 1950 patients with PD and 2073 healthy controls from three studies. There was significant association between rs591323 and the risk of PD in the additive (Z = −3.96; p < 0.0001) and the dominant models (Z = −4.01; p < 0.0001). Our study results and the meta-analysis support the possible protective role of the rs591323 A allele in PD in Taiwanese/Chinese populations.

Download Full-text

Potential role of protein stabilizers in amelioration of Parkinson's disease and associated effects in transgenic Caenorhabditis elegans model expressing alpha-synuclein

RSC Advances ◽

10.1039/c5ra13546j ◽

2015 ◽

Vol 5 (95) ◽

pp. 77706-77715 ◽

Cited By ~ 4

Author(s):

Supinder Kaur ◽

Aamir Nazir

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Caenorhabditis Elegans ◽

Potential Role ◽

Alpha Synuclein ◽

C Elegans

Studies employing transgenicC. elegansmodel show that trehalose, a protein stabilizer, alleviates manifestations associated with Parkinson's diseaseviaits inherent activity and through induction of autophagic machinery.

Download Full-text