Does human alpha synuclein behave like prions?

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.

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

2018 ◽  
Author(s):  
Tim E. Moors ◽  
Christina A. Maat ◽  
Daniel Niedieker ◽  
Daniel Mona ◽  
Dennis Petersen ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Lewy Bodies ◽  
Distribution Patterns ◽  
Alpha Synuclein ◽  
Label Free ◽  
Post Translational Modifications ◽  
Sted Microscopy ◽  
C Terminus

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.

scholarly journals Association Between Decreased Srpk3 Expression And An Increase In Substantia Nigra Alpha-Synuclein Levels In An MPTP-Induced Parkinson’s Disease Mouse Model

2022 ◽  
Author(s):  
Min Hyung Seo ◽  
Sujung Yeo
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Substantia Nigra ◽  
Dopaminergic Neurons ◽  
Cell Loss ◽  
Alpha Synuclein ◽  
Mice Model ◽  
Dopaminergic Cell ◽  
The Brain

Abstract Parkinson’s disease (PD) is known as the second most common neurodegenerative disease, which is caused by destruction of dopaminergic neurons in the substantia nigra (SN) of the brain; however, the reason for the death of dopaminergic neurons remains unclear. An increase in α-synuclein (α-syn) is considered an important factor in the pathogenesis of PD. In the current study, we investigated the association between PD and serine/arginine-rich protein specific kinase 3 (Srpk3) in MPTP-induced parkinsonism mice model and in SH-SY5Y cells treated with MPP+. Srpk3 expression was significantly downregulated, while tyrosine hydroxylase (TH) decreased and α-synuclein (α-syn) increased after 4 weeks of MPTP intoxication treatment. Dopaminergic cell reduction and α-syn increase were demonstrated by inhibiting Srpk3 expression by siRNA in SH-SY5Y cells. Moreover, a decrease in Srpk3 expression upon siRNA treatment promoted dopaminergic cell reduction and α-syn increase in SH-SY5Y cells treated with MPP+. These results suggest that the decrease in Srpk3 expression due to Srpk3 siRNA caused both a decrease in TH and an increase in α-syn. This raises new possibilities for studying how Srpk3 controls dopaminergic cells and α-syn expression, which may be related to the pathogenesis of PD. Our results provide an avenue for understanding the role of Srpk3 during dopaminergic cell loss and α-syn increase in the SN. Furthermore, this study could support a therapeutic possibility for PD in that the maintenance of Srpk3 expression inhibited dopaminergic cell reduction.

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

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.

scholarly journals Alpha-Synuclein: The Interplay of Pathology, Neuroinflammation, and Environmental Factors in Parkinson’s Disease

2020 ◽  
Vol 20 (2-3) ◽  
pp. 55-64
Author(s):  
Songzhe He ◽  
Shan Zhong ◽  
Gang Liu ◽  
Jun Yang
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Environmental Factors ◽  
Dopaminergic Neurons ◽  
Molecular Mechanisms ◽  
Lewy Bodies ◽  
Alpha Synuclein ◽  
Future Directions ◽  
Main Protein ◽  
Cumulative Evidence

<b><i>Background:</i></b> Parkinson’s disease (PD) is a multifactorial, chronic, and progressive neurodegenerative disease. α-Synuclein (α-syn), which is the main protein component of Lewy bodies, plays an important role in the pathological hallmarks of PD. However, the pathological function of α-syn and the molecular mechanisms responsible for the degeneration of dopaminergic neurons are still elusive. <b><i>Summary:</i></b> Cumulative evidence implicates that abnormal processing of α-syn will be predicted to lead to pathological changes in PD. <b><i>Key Messages:</i></b> In this review, we summarize the structure and physiological function of α-syn, and further discuss the interplay of pathology, neuroinflammation, and environmental factors in PD. Additionally, we suggest future directions for understanding the toxicity of α-syn to neurons, which may ultimately encourage us to better design disease-modifying therapeutic strategies for PD.

scholarly journals α-Synuclein facilitates endocytosis by elevating the steady-state levels of phosphatidylinositol 4,5-bisphosphate

2020 ◽  
Author(s):  
Schechter Meir ◽  
Atias Merav ◽  
Abd Elhadi Suaad ◽  
Davidi Dana ◽  
Gitler Daniel ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Plasma Membrane ◽  
Membrane Trafficking ◽  
Synaptic Vesicles ◽  
Causative Role ◽  
Coated Pits ◽  
Exact Role ◽  
Intrinsically Disordered

Abstractα-Synuclein (α-Syn) is a protein implicated in the pathogenesis of Parkinson’s disease (PD). It is an intrinsically disordered protein that binds acidic phospholipids. Growing evidence supports a role for α-Syn in membrane trafficking, including, mechanisms of endocytosis and exocytosis, although the exact role of α-Syn in these mechanisms is currently unclear. Here we have investigated the role of α-Syn in membrane trafficking through its association with acidic phosphoinositides (PIPs), such as phosphatidylinositol 4,5-bisphosphate (PI4,5P2) and phosphatidylinositol 3,4-bisphosphate (PI3,4P2). Our results show that α-Syn colocalizes with PIP2 and the phosphorylated active form of the clathrin adaptor AP2 at clathrin-coated pits. Using endocytosis of transferrin, an indicator of clathrin mediated endocytosis (CME), we find that α-Syn involvement in endocytosis is specifically mediated through PI4,5P2 levels. We further show that the rate of synaptic vesicle (SV) endocytosis is differentially affected by α-Syn mutations. In accord with their effects on PI4,5P2 levels at the plasma membrane, the PD associated E46K and A53T mutations further enhance SV endocytosis. However, neither A30P mutation, nor Lysine to Glutamic acid substitutions at the KTKEGV repeat domain of α-Syn, that interfere with phospholipid binding, affect SV endocytosis. This study provides evidence for a critical involvement of PIPs in α-Syn-mediated membrane trafficking.Significance Statementα-Synuclein (α-Syn) protein is known for its causative role in Parkinson’s disease. α-Syn is normally involved in mechanisms of membrane trafficking, including endocytosis, exocytosis and synaptic vesicles cycling. However, a certain degree of controversy regarding the exact role of α-Syn in these mechanisms persists. Here we show that α-Syn acts to increase plasma membrane levels PI4,5P2 and PI3,4P2 to facilitate clathrin mediated and synaptic vesicles endocytosis. Based on the results, we suggest that α-Syn interactions with the acidic phosphoinositides facilitate a shift in their homeostasis to support endocytosis.

scholarly journals Alpha synuclein aggresomes inhibit ciliogenesis and multiple functions of the centrosome

2019 ◽  
Author(s):  
Anila Iqbal ◽  
Marta Baldrighi ◽  
Jennifer N. Murdoch ◽  
Angeleen Fleming ◽  
Christopher J. Wilkinson
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Dopaminergic Neurons ◽  
Intracellular Transport ◽  
Neuronal Cell Death ◽  
Lewy Bodies ◽  
Neuronal Cell ◽  
Cell Types ◽  
Alpha Synuclein ◽  
Microtubule Network

AbstractProtein aggregates are the pathogenic hallmarks of many different neurodegenerative diseases and include the Lewy bodies found in Parkinson’s disease. Aggresomes are closely-related cellular accumulations of misfolded proteins. They develop in a juxtanuclear position, adjacent to the centrosome, the microtubule organizing centre of the cell, and share some protein components. Despite the long-standing observation that aggresomes/Lewy bodies and the centrosome sit side-by-side in the cell, no studies have been done to see whether these protein accumulations impede the organelle function. We investigated whether the formation of aggresomes affected key centrosome functions: its ability to organize the microtubule network and to promote cilia formation. We find that when aggresomes are present, neuronal cells are unable to organise their microtubule network. New microtubules are not nucleated and extended, and the cells fail to respond to polarity cues. Since dopaminergic neurons are polarised, ensuring correct localisation of organelles and the effective intracellular transport of neurotransmitter vesicles, loss of centrosome activity could contribute to loss of dopaminergic function and neuronal cell death in Parkinson’s disease. In addition, we provide evidence that many cell types, including dopaminergic neurons, cannot form cilia when aggresomes are present, which would affect their ability to receive extracellular signals.

scholarly journals Role of neuron specific enolase as a biomarker in Parkinson’s disease

2021 ◽  
Vol 5 (2) ◽  
pp. 061-068
Author(s):  
Dutta Rajib
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Dopaminergic Neurons ◽  
Neuron Specific Enolase ◽  
Alpha Synuclein ◽  
Substantia Nigra Pars Compacta ◽  
Diagnostic Tools ◽  
Clinical Image ◽  
Motor Symptoms

Parkinson’s disease (PD) is thought to be the most common neurodegenerative disease with movement disorder. The key motor symptoms are rigidity, tremor, akinesis/hypokinesia/bradykinesia, and postural instability. However, in our day-to-day clinical practice we tend to see several other symptoms which may be motor or non-motor. Non-motor symptoms (NMS) are quite common and debilitating. The pathological hallmarks of PD are loss of dopaminergic neurons in the substantia nigra pars compacta (SNPc) and accumulation of unfolded or misfolded alpha-synuclein. Diagnosis of PD is difficult in the pre-motor stage. Late diagnosis renders a substantial loss of dopaminergic neurons in SNPc and spread of disease in other parts of the brain. This may manifest as either full blown symptoms requiring multiple medications or may even lead to life threatening condition due to lack of early diagnostic tools and techniques. Biomarkers are required to diagnose PD at a very early stage when prevention is possible. Hence, we see a lot of interest among researchers involved in finding a biomarker specific to the disease. Biomarkers may be clinical, image based, genetic, and biochemical. Cerebrospinal fluid (CSF) and serum markers which may correlate with disease pathophysiology are of great significance. One such molecule which recently gained a lot of attention is neuron-specific enolase (NSE). The main aim of this paper is to highlight the role of NSE in predicting neurodegeneration and neuroinflammation ultimately reflecting damage of brain cells in PD.

scholarly journals The role of natural killer cells in Parkinson’s disease

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.

scholarly journals Quality Control of Mitochondria in Parkinson's Disease (PD) Using ATP And Bradford Assays

2022 ◽  
Author(s):  
Al-Baraa Akram
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Quality Control ◽  
Dopaminergic Neurons ◽  
Complex Disease ◽  
Motor Impairment ◽  
Lewy Bodies ◽  
Protease Gene ◽  
Mitochondrial Quality Control

Abstract Parkinson's disease is a heterogeneous, multifactorial and often complex disease characterized by motor impairment due to the presence of Lewy bodies and prominent degeneration of dopaminergic neurons in the substantia nigra. Although the specific pathogenesis involving PD remains under investigation, mitochondrial dysfunction has been widely accepted as one of the major pathogenic pathways underlying the development of PD. Based on the hypothesis that depiction of HtrA2 (serine protease gene, mitochondrial precursor) might contribute to an increase in mitochondrial stress and transcriptional upregulation of the nuclear stress-response CHOP gene. The present study aimed to analyze through laboratory-based research the role of HtrA2 and CHOP in the transmission of stress signaling and the consequent activation of mitochondrial quality control in Parkinson's disease using ATP and Bradford assays.

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