scholarly journals Alpha-Synuclein Preserves Mitochondrial Fusion and Function in Neuronal Cells

2019 ◽  
Vol 2019 ◽  
pp. 1-11 ◽  
Author(s):  
Gaia Faustini ◽  
Elena Marchesan ◽  
Laura Zonta ◽  
Federica Bono ◽  
Emanuela Bottani ◽  
...  
Keyword(s):  
Cortical Neurons ◽  
Neurodegenerative Disorder ◽  
Lewy Bodies ◽  
Alpha Synuclein ◽  
Physical Interaction ◽  
Primary Cortical Neurons ◽  
Altered Expression ◽  
Extracellular Flux ◽  
Mitochondrial Functions ◽  
And Function

Dysregulations of mitochondria with alterations in trafficking and morphology of these organelles have been related to Parkinson’s disease (PD), a neurodegenerative disorder characterized by brain accumulation of Lewy bodies (LB), intraneuronal inclusions mainly composed of α-synuclein (α-syn) fibrils. Experimental evidence supports that α-syn pathological aggregation can negatively impinge on mitochondrial functions suggesting that this protein may be crucially involved in the control of mitochondrial homeostasis. The aim of this study was to assay this hypothesis by analyzing mitochondrial function and morphology in primary cortical neurons from C57BL/6JOlaHsd α-syn null and C57BL/6J wild-type (wt) mice. Primary cortical neurons from mice lacking α-syn showed decreased respiration capacity measured with a Seahorse XFe24 Extracellular Flux Analyzer. In addition, morphological Airyscan superresolution microscopy showed the presence of fragmented mitochondria while real-time PCR and western blot confirmed altered expression of proteins involved in mitochondrial shape modifications in the primary cortical neurons of α-syn null mice. Transmission electron microscopy (TEM) studies showed that α-syn null neurons exhibited impaired mitochondria-endoplasmic reticulum (ER) physical interaction. Specifically, we identified a decreased number of mitochondria-ER contacts (MERCs) paralleled by a significant increase in ER-mitochondria distance (i.e., MERC length). These findings support that α-syn physiologically preserves mitochondrial functions and homeostasis. Studying α-syn/mitochondria interplay in health and disease is thus pivotal for understanding their involvement in PD and other LB disorders.

scholarly journals The Catecholaldehyde Hypothesis for the Pathogenesis of Catecholaminergic Neurodegeneration: What We Know and What We Do Not Know

2021 ◽  
Vol 22 (11) ◽  
pp. 5999
Author(s):  
David S. Goldstein
Keyword(s):  
Lewy Bodies ◽  
Alpha Synuclein ◽  
Future Research ◽  
Catecholamine Metabolism ◽  
Secondary Effects ◽  
Drug Induced ◽  
Neuronal Homeostasis ◽  
Mitochondrial Functions ◽  
Environmental Agents ◽  
Spontaneous Oxidation

3,4-Dihydroxyphenylacetaldehyde (DOPAL) is the focus of the catecholaldehyde hypothesis for the pathogenesis of Parkinson’s disease and other Lewy body diseases. The catecholaldehyde is produced via oxidative deamination catalyzed by monoamine oxidase (MAO) acting on cytoplasmic dopamine. DOPAL is autotoxic, in that it can harm the same cells in which it is produced. Normally, DOPAL is detoxified by aldehyde dehydrogenase (ALDH)-mediated conversion to 3,4-dihydroxyphenylacetic acid (DOPAC), which rapidly exits the neurons. Genetic, environmental, or drug-induced manipulations of ALDH that build up DOPAL promote catecholaminergic neurodegeneration. A concept derived from the catecholaldehyde hypothesis imputes deleterious interactions between DOPAL and the protein alpha-synuclein (αS), a major component of Lewy bodies. DOPAL potently oligomerizes αS, and αS oligomers impede vesicular and mitochondrial functions, shifting the fate of cytoplasmic dopamine toward the MAO-catalyzed formation of DOPAL—destabilizing vicious cycles. Direct and indirect effects of DOPAL and of DOPAL-induced misfolded proteins could “freeze” intraneuronal reactions, plasticity of which is required for neuronal homeostasis. The extent to which DOPAL toxicity is mediated by interactions with αS, and vice versa, is poorly understood. Because of numerous secondary effects such as augmented spontaneous oxidation of dopamine by MAO inhibition, there has been insufficient testing of the catecholaldehyde hypothesis in animal models. The clinical pathophysiological significance of genetics, emotional stress, environmental agents, and interactions with numerous proteins relevant to the catecholaldehyde hypothesis are matters for future research. The imposing complexity of intraneuronal catecholamine metabolism seems to require a computational modeling approach to elucidate clinical pathogenetic mechanisms and devise pathophysiology-based, individualized treatments.

Are lysosomes potential therapeutic targets for Parkinson’s disease?

2021 ◽  
Vol 20 ◽  
Author(s):  
A. Petese ◽  
V. Cesaroni ◽  
S. Cerri ◽  
F. Blandini
Keyword(s):  
Neurodegenerative Disorder ◽  
Association Studies ◽  
Lewy Bodies ◽  
Alpha Synuclein ◽  
Genome Wide Association Studies ◽  
Lysosomal Dysfunction ◽  
Genome Wide ◽  
Nigrostriatal Neurons ◽  
Disease Modifying Treatment ◽  
Alpha Synuclein Aggregation

Background: Parkinson´s disease (PD) is the second most common neurodegenerative disorder, affecting 2-3% of the population over 65 years old. In addition to progressive degeneration of nigrostriatal neurons, the histopathological feature of PD is the accumulation of misfolded α-synuclein protein in abnormal cytoplasmatic inclusions, known as Lewy bodies (LBs). Recently, genome-wide association studies (GWAS) have indicated a clear association of variants within several lysosomal genes with risk for PD. Newly evolving data have been shedding light on the relationship between lysosomal dysfunction and alpha-synuclein aggregation. Defects in lysosomal enzymes could lead to the insufficient clearance of neurotoxic protein materials, possibly leading to selective degeneration of dopaminergic neurons. Specific modulation of lysosomal pathways and their components could be considered a novel opportunity for therapeutic intervention for PD. Aim: The purpose of this review is to illustrate lysosomal biology and describe the role of lysosomal dysfunction in PD pathogenesis. Finally, the most promising novel therapeutic approaches designed to modulate lysosomal activity, as a potential disease-modifying treatment for PD will be highlighted.

scholarly journals (De)stabilization of Alpha-Synuclein Fibrillary Aggregation by Charged and Uncharged Surfactants

2021 ◽  
Vol 22 (22) ◽  
pp. 12509
Author(s):  
Joana Angélica Loureiro ◽  
Stéphanie Andrade ◽  
Lies Goderis ◽  
Ruben Gomez-Gutierrez ◽  
Claudio Soto ◽  
...  
Keyword(s):  
Secondary Structure ◽  
Hydrophobic Interactions ◽  
Neurodegenerative Disorder ◽  
Sodium Dodecyl ◽  
Lewy Bodies ◽  
Alpha Synuclein ◽  
Cetyltrimethylammonium Chloride ◽  
Α Helix ◽  
Β Sheet

Parkinson’s disease (PD) is the second most common neurodegenerative disorder. An important hallmark of PD involves the pathological aggregation of proteins in structures known as Lewy bodies. The major component of these proteinaceous inclusions is alpha (α)-synuclein. In different conditions, α-synuclein can assume conformations rich in either α-helix or β-sheets. The mechanisms of α-synuclein misfolding, aggregation, and fibrillation remain unknown, but it is thought that β-sheet conformation of α-synuclein is responsible for its associated toxic mechanisms. To gain fundamental insights into the process of α-synuclein misfolding and aggregation, the secondary structure of this protein in the presence of charged and non-charged surfactant solutions was characterized. The selected surfactants were (anionic) sodium dodecyl sulphate (SDS), (cationic) cetyltrimethylammonium chloride (CTAC), and (uncharged) octyl β-D-glucopyranoside (OG). The effect of surfactants in α-synuclein misfolding was assessed by ultra-structural analyses, in vitro aggregation assays, and secondary structure analyses. The α-synuclein aggregation in the presence of negatively charged SDS suggests that SDS-monomer complexes stimulate the aggregation process. A reduction in the electrostatic repulsion between N- and C-terminal and in the hydrophobic interactions between the NAC (non-amyloid beta component) region and the C-terminal seems to be important to undergo aggregation. Fourier transform infrared spectroscopy (FTIR) measurements show that β-sheet structures comprise the assembly of the fibrils.

scholarly journals Treating Parkinson’s Disease with Antibodies: Previous Studies and Future Directions

2020 ◽  
pp. 1-22
Author(s):  
Anne-Marie Castonguay ◽  
Claude Gravel ◽  
Martin Lévesque
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Neurodegenerative Disorder ◽  
Passive Immunization ◽  
Lewy Bodies ◽  
Gene Mutations ◽  
Alpha Synuclein ◽  
Multiple Sources ◽  
Immunization Strategies ◽  
A Cell

Parkinson’s disease is a neurodegenerative disorder mainly characterized by the degeneration of dopaminergic neurons in the substantia nigra. Degenerating neurons contain abnormal aggregates called Lewy bodies, that are predominantly composed of the misfolded and/or mutated alpha-synuclein protein. Post-translational modifications, cellular stress, inflammation and gene mutations are thought to trigger its pathological misfolding and aggregation. With alpha-synuclein pathology being strongly associated with dopaminergic neuronal toxicity, strategies aimed to reduce its burden are expected to be beneficial in slowing disease progression. Moreover, multiple sources of evidence suggest a cell-to-cell transmission of pathological alpha-synuclein in a prion-like manner. Therefore, antibodies targeting extra- or intracellular alpha-synuclein could be efficient in limiting the aggregation and transmission. Several active and passive immunization strategies have been explored to target alpha-synuclein. Here, we summarize immunotherapeutic approaches that were tested in pre-clinical or clinical studies in the last two decades in an attempt to treat Parkinson’s disease.

scholarly journals Potential Effects of Leukotriene Receptor Antagonist Montelukast in Treatment of Neuroinflammation in Parkinson’s Disease

2021 ◽  
Vol 22 (11) ◽  
pp. 5606
Author(s):  
Johan Wallin ◽  
Per Svenningsson
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Receptor Antagonist ◽  
Neurodegenerative Disorder ◽  
Lewy Bodies ◽  
Adaptive Immune System ◽  
Alpha Synuclein ◽  
Leukotriene Receptor Antagonist ◽  
Leukotriene Receptor ◽  
Immune Changes

Parkinson’s disease (PD) is a neurodegenerative disorder where misfolded alpha-synuclein-enriched aggregates called Lewy bodies are central in pathogenesis. No neuroprotective or disease-modifying treatments are currently available. Parkinson’s disease is considered a multifactorial disease and evidence from multiple patient studies and animal models has shown a significant immune component during the course of the disease, highlighting immunomodulation as a potential treatment strategy. The immune changes occur centrally, involving microglia and astrocytes but also peripherally with changes to the innate and adaptive immune system. Here, we review current understanding of different components of the PD immune response with a particular emphasis on the leukotriene pathway. We will also describe evidence of montelukast, a leukotriene receptor antagonist, as a possible anti-inflammatory treatment for PD.

scholarly journals Alpha-synuclein is present in the nucleus in human brain tissue and is pathologically modified in Dementia with Lewy Bodies

2021 ◽  
Author(s):  
David J Koss ◽  
Daniel Erskine ◽  
Andrew Porter ◽  
Marta Leite ◽  
Johannes Attems ◽  
...  
Keyword(s):  
Human Brain ◽  
Brain Tissue ◽  
Cortical Neurons ◽  
Dementia With Lewy Bodies ◽  
Neuronal Cells ◽  
Lewy Bodies ◽  
Disease Process ◽  
Alpha Synuclein ◽  
Dna Integrity ◽  
Human Brain Tissue

Background Dementia with Lewy bodies (DLB) is pathologically-defined by the cytoplasmic accumulation of alpha-synuclein (aSyn) within neuronal cells in the brain. aSyn is predominately pre-synaptic, but has been reported present in various subcellular compartments in cell and animal models. In particular, nuclear aSyn (aSynNuc) is evident in-vitro and in disease models and has been associated with altered DNA integrity, gene transcription, nuclear homeostasis. However, owing to various factors, the presence of aSynNuc in the human brain remains controversial, as does its role in synucleinopathies. Methods Here, we close this gap and provide a unique demonstration confirming the presence of aSynNuc in control (Con) and in DLB post-mortem brain tissue via immunohistochemistry, immunoblot, and label-free mass-spectrometry (MS). Results Discrete intra-nuclear aSyn puncta reactive against phosphorylated serine 129-aSyn (pS129-aSyn) and pan-aSyn antibodies were observed in cortical neurons and non-neuronal cells in fixed brain sections and isolated nuclear preparations from Con and DLB cases. Subsequent biochemical analysis of subcellular fractionated tissue confirmed aSynNuc as present at levels ~10-fold lower than in the cytoplasm. Critically, however, an increase in monomeric pS129-aSyn was observed in DLB cases alongside higher molecular weight pan- and pS129-reactive aSyn species, consistent with the formation of intranuclear phosphorylated aSynNuc oligomers. Furthermore, the occurrence of aSynNuc was confirmed via MS, with 6 unique aSyn derived peptide sequences identified in nuclear fractions (71.4% aSyn sequence coverage). Conclusions Collectively, our data confirm the presence of aSynNuc in human brain tissue and describe DLB-associated nuclear pathology. These findings address a major controversy in the synucleinopathy field by confirming the presence of aSynNuc in autoptic human brain tissue and, for the first time, identify that aSyn is aggregated into novel and potentially pathological assemblies in the nucleus as part of the DLB disease process and thus may contribute to the DLB phenotype.

scholarly journals Neurotrophic factors for disease-modifying treatments of Parkinson's disease: gaps between basic science and clinical studies

2020 ◽  
Vol 72 (5) ◽  
pp. 1195-1217
Author(s):  
Piotr Chmielarz ◽  
Mart Saarma
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Neurotrophic Factors ◽  
Neurodegenerative Disorder ◽  
Lewy Bodies ◽  
Underlying Disease ◽  
Alpha Synuclein ◽  
Dopamine Neurons ◽  
Neural Cells ◽  
Disease Etiology

Abstract Background Neurotrophic factors are endogenous proteins promoting the survival of different neural cells. Therefore, they elicited great interest as a possible treatment for neurodegenerative disorders, including Parkinson’s Disease (PD). PD is the second most common neurodegenerative disorder, scientifically characterized more than 200 years ago and initially linked with motor abnormalities. Currently, the disease is viewed as a highly heterogeneous, progressive disorder with a long presymptomatic phase, and both motor and non-motor symptoms. Presently only symptomatic treatments for PD are available. Neurohistopathological changes of PD affected brains have been described more than 100 years ago and characterized by the presence of proteinaceous inclusions known as Lewy bodies and degeneration of dopamine neurons. Despite more than a century of investigations, it has remained unclear why dopamine neurons die in PD. Methods This review summarizes literature data from preclinical studies and clinical trials of neurotrophic factor based therapies for PD and discuss it from the perspective of the current understanding of PD biology. Results Newest data point towards dysfunctions of mitochondria, autophagy-lysosomal pathway, unfolded protein response and prion protein-like spreading of misfolded alpha-synuclein that is the major component of Lewy bodies. Yet, the exact chain of events leading to the demise of dopamine neurons is unclear and perhaps different in subpopulations of patients. Conclusions Gaps in our understanding of underlying disease etiology have hindered our attempts to find treatments able to slow down the progression of PD. Graphic abstract

scholarly journals Expression of transduced Nucleolin promotes the clearance of accumulated alpha-synuclein

2020 ◽  
Author(s):  
DONG HWAN HO ◽  
Daleum Nam ◽  
Soyeon Jeong ◽  
Mi Kyoung Seo ◽  
Sung Woo Park ◽  
...  
Keyword(s):  
Substantia Nigra ◽  
Cortical Neurons ◽  
Opposite Effect ◽  
Fluorescent Protein ◽  
Ectopic Expression ◽  
Lewy Bodies ◽  
Alpha Synuclein ◽  
Embryonic Fibroblasts ◽  
Nucleolar Structure ◽  
Green Fluorescent

Abstract Background Alpha-synuclein (αSyn) is a major component of Lewy bodies, which are known to be a pathogenic marker of Parkinson’s disease (PD). The accumulation of αSyn is caused by dysfunctions in protein degradation machinery. The reinforcement of αSyn degradation is a potential therapeutic target of PD since accumulated αSyn is responsible for the pathogenesis of PD. Nucleolin (NCL) is essential for forming nucleolar structure. The function of NCL is correlated with oxidative stress-mediated cell death. A previous study demonstrated that NCL was reduced in PD brains, and overexpression of NCL alleviated rotenone-induced neural toxic effects. Knockdown of NCL had the opposite effect. These results suggest that the malfunctioning of NCL would exacerbate PD pathology. Thus, we hypothesized that the introduction of ectopic NCL could rescue the α-synucleinopathy in PD. Methods We tested whether ectopic expression of NCL facilitates the clearance of αSyn. The Ectopic expression of NCL was accomplished by the transfection of GFP or GFP-NCL in mouse embryonic fibroblasts (MEF) or transduction of green fluorescent protein (GFP) or GFP-NCL using lentivirus in rat primary cortical neuron. We also investigated whether the expression of GFP or GFP-NCL in mouse substantia nigra alleviates the PD pathology derived by αSyn aggregates. Results The expression of NCL enhanced the clearance of αSyn accumulation or aggregates in MEF and rat primary cortical neurons. The activity of autophagy-lysosome pathway was enhanced by NCL expression. The transduction of NCL in the substantia nigra, which was co-injected with αSyn fibrils, rescued PD manifestations. Conclusions The elevation of NCL levels may reflect a therapeutic strategy for α-synucleinopathy in PD.

849 REM Behavioral Disorder as a Predictor of Lewy body Dementia- A Case Report

SLEEP ◽  
2021 ◽  
Vol 44 (Supplement_2) ◽  
pp. A330-A330
Author(s):  
Rupa Koothirezhi ◽  
Pratibha Anne ◽  
Minh Tam Ho ◽  
Brittany Monceaux ◽  
Cesar Liendo ◽  
...  
Keyword(s):  
Clinical Features ◽  
Lewy Body ◽  
Neurodegenerative Disorder ◽  
Lewy Bodies ◽  
Rem Sleep Behavior Disorder ◽  
Lewy Body Dementia ◽  
Alpha Synuclein ◽  
Behavioral Disorder ◽  
Sleep Behavior ◽  
Obstructive Sleep

Abstract Introduction Dementia with Lewy bodies (DLB) is one of the most common types of degenerative dementia after Alzheimer’s dementia. The core clinical features for diagnosis includes cognitive fluctuations, visual hallucinations, rapid eye movement (REM) sleep behavior disorder (RBD), and parkinsonism. Other symptoms include daytime drowsiness, longer daytime naps, prolonged staring spells, and episodes of disorganized speech. REM behavioral disorder (RBD) is commonly associated with DLB, occurring in 85 percent of individuals, often early in the course of the disease. It can precede the clinical diagnosis of DLB by up to 20 years. Report of case(s) A seventy-six-year-old female with a history of well controlled obstructive sleep apnea was diagnosed with REM behavioral disorder in 2012. She had presented with episodes of screaming, attempt to ambulate during sleep, resulting in injury. Her polysomnogram revealed evidence of REM without atonia and a screaming episode during REM. Her RBD symptoms were controlled with clonazepam and melatonin with less frequency of the RBD episodes. The patient gradually started noticing memory issues and by January 2020 she was diagnosed with dementia and was initiated on Aricept. Within 7 months of diagnosis of dementia, she started reporting vivid hallucinations that were not threatening or violent compared to her violent content of RBD. Physical exam revealed impaired cognitive function and mild intermittent resting tremor of the right hand. The neurological exam was normal including normal tone, strength, and gait. She also reported repeated falls and fractures. The diagnosis of Lewy body dementia was made based on the presence of 2 core clinical features. Conclusion The current management of these conditions is mainly symptomatic. In the evolution of neurodegenerative disorder, RBD precedes other conditions like LBD, parkinsonism, etc. Research suggests that alpha-synuclein neurodegeneration is the common pathology behind these conditions. The understanding that RBD presents at the beginning of the evolution, provides us with a unique opportunity for preemptive treatment to prevent further degeneration in turn preventing the debilitation consequence like dementia, parkinsonism, neuroleptic sensitivity, and dysautonomia. Further research is needed for developing these early interventional strategies. Support (if any) NOne

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