scholarly journals The Convergence of Alpha-Synuclein, Mitochondrial, and Lysosomal Pathways in Vulnerability of Midbrain Dopaminergic Neurons in Parkinson’s Disease

2020 ◽  
Vol 8 ◽  
Author(s):  
Georgia Minakaki ◽  
Dimitri Krainc ◽  
Lena F. Burbulla
Keyword(s):  
Oxidative Stress ◽  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Alpha Synuclein ◽  
Motor Symptoms ◽  
Intracellular Iron ◽  
Therapeutic Benefits ◽  
Midbrain Dopaminergic Neurons ◽  
Midbrain Dopamine ◽  
Key Events

Parkinson’s disease (PD) is the second most common neurodegenerative disease, characterized by progressive bradykinesia, rigidity, resting tremor, and gait impairment, as well as a spectrum of non-motor symptoms including autonomic and cognitive dysfunction. The cardinal motor symptoms of PD stem from the loss of substantia nigra (SN) dopaminergic (DAergic) neurons, and it remains unclear why SN DAergic neurons are preferentially lost in PD. However, recent identification of several genetic PD forms suggests that mitochondrial and lysosomal dysfunctions play important roles in the degeneration of midbrain dopamine (DA) neurons. In this review, we discuss the interplay of cell-autonomous mechanisms linked to DAergic neuron vulnerability and alpha-synuclein homeostasis. Emerging studies highlight a deleterious feedback cycle, with oxidative stress, altered DA metabolism, dysfunctional lysosomes, and pathological alpha-synuclein species representing key events in the pathogenesis of PD. We also discuss the interactions of alpha-synuclein with toxic DA metabolites, as well as the biochemical links between intracellular iron, calcium, and alpha-synuclein accumulation. We suggest that targeting multiple pathways, rather than individual processes, will be important for developing disease-modifying therapies. In this context, we focus on current translational efforts specifically targeting lysosomal function, as well as oxidative stress via calcium and iron modulation. These efforts could have therapeutic benefits for the broader population of sporadic PD and related synucleinopathies.

scholarly journals Alpha-Synuclein Oligomers Interact with Metal Ions to Induce Oxidative Stress and Neuronal Death in Parkinson's Disease

2016 ◽  
Vol 24 (7) ◽  
pp. 376-391 ◽  
Author(s):  
Emma Deas ◽  
Nunilo Cremades ◽  
Plamena R. Angelova ◽  
Marthe H.R. Ludtmann ◽  
Zhi Yao ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Metal Ions ◽  
Neuronal Death ◽  
Alpha Synuclein

scholarly journals Mitochondria interaction networks show altered topological patterns in Parkinson’s disease

2020 ◽  
Vol 6 (1) ◽  
Author(s):  
Massimiliano Zanin ◽  
Bruno F. R. Santos ◽  
Paul M. A. Antony ◽  
Clara Berenguer-Escuder ◽  
Simone B. Larsen ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Point Mutations ◽  
Interaction Network ◽  
Critical Dimension ◽  
Alpha Synuclein ◽  
Interaction Networks ◽  
Scale Free ◽  
Midbrain Dopaminergic Neurons ◽  
Highly Correlated

Abstract Mitochondrial dysfunction is linked to pathogenesis of Parkinson’s disease (PD). However, individual mitochondria-based analyses do not show a uniform feature in PD patients. Since mitochondria interact with each other, we hypothesize that PD-related features might exist in topological patterns of mitochondria interaction networks (MINs). Here we show that MINs formed nonclassical scale-free supernetworks in colonic ganglia both from healthy controls and PD patients; however, altered network topological patterns were observed in PD patients. These patterns were highly correlated with PD clinical scores and a machine-learning approach based on the MIN features alone accurately distinguished between patients and controls with an area-under-curve value of 0.989. The MINs of midbrain dopaminergic neurons (mDANs) derived from several genetic PD patients also displayed specific changes. CRISPR/CAS9-based genome correction of alpha-synuclein point mutations reversed the changes in MINs of mDANs. Our organelle-interaction network analysis opens another critical dimension for a deeper characterization of various complex diseases with mitochondrial dysregulation.

scholarly journals Dynamic changes in the CD163+ and CCR2+ peripheral monocytes during Parkinson’s disease

2021 ◽  
Author(s):  
Sara Konstantin Nissen ◽  
Kristine Farmen ◽  
Mikkel Carstensen ◽  
Claudia Schulte ◽  
David Goldeck ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Dendritic Cells ◽  
Alpha Synuclein ◽  
Mononuclear Phagocytes ◽  
Motor Symptoms ◽  
Hla Dr ◽  
Non Motor Symptoms ◽  
The Brain ◽  
Classical Monocytes

AbstractBackgroundAlpha-synuclein aggregates and accumulation are associated with immune activation and neurodegeneration in Parkinson’s disease. The immune activation is not only dependent on the brain-resident microglial cells but also involves peripheral immune cells, such as mononuclear phagocytes including monocytes and dendritic cells, found in the blood as well as infiltrated into the brain. Understanding the involvement of the peripheral immune component in Parkinson’s disease is essential for the development of immunomodulatory treatment, which might modify disease progression. We aimed to study the profile of circulating mononuclear phagocytes in early- and late-stage Parkinson’s disease by analyzing surface-expressed molecules related to phagocytosis, alpha-synuclein sensing, and tissue-migration.MethodsMulti-color flow cytometry on peripheral mononuclear cells from cross-sectional samples of 80 gender-balance individuals with early- and late-stage sporadic Parkinson’s disease, and 29 controls, as well as longitudinal samples from seven patients and one control. Cells were delineated into natural killer cells, monocyte subtypes, and dendritic cells with cell frequencies and surface marker expressions compared between patients and controls, and correlated with standardized clinical motor and non-motor scores.ResultsOverall, we found elevated frequencies and surface levels of markers related to migration (CCR2, CD11b) and phagocytosis (CD163) particularly on the elevated classical and intermediate monocytes in patients with Parkinson’s disease for less than five years. This corresponded to a decrease of non-classical monocytes and dendritic cells. We observed an increased HLA-DR expression late in disease and sexual-dimorphism with TLR-4 expression decreased in women with PD but not in males. The disease-associated immune changes on TLR4, CCR2, and CD11b were correlated with non-motor symptoms such as olfaction or cognition. While many alterations were normalized at late disease stage, other changes remained, such as the increased HLA-DR and CD163 expressions.ConclusionsOur data highlight a role for peripheral CD163+ and migration-competent classical monocytes in Parkinson’s disease. The study further suggests that the peripheral immune system is dynamically altered in Parkinson’s disease stages and directly related to both non-motor symptoms and the sex-bias of the disease.

scholarly journals Transgenic mice expressing human alpha-synuclein in noradrenergic neurons develop locus coeruleus pathology and non-motor features of Parkinson’s disease

2019 ◽  
Author(s):  
LM Butkovich ◽  
MC Houser ◽  
T Chalermpalanupap ◽  
KA Porter-Stransky ◽  
AF Iannitelli ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Transgenic Mice ◽  
Locus Coeruleus ◽  
Transgenic Mouse ◽  
Alpha Synuclein ◽  
Striatal Dopamine ◽  
Motor Symptoms ◽  
Age Dependent ◽  
Non Motor Symptoms

AbstractDegeneration of locus coeruleus (LC) neurons and dysregulation of noradrenergic signaling are ubiquitous features of Parkinson’s disease (PD). The LC is among the first brain regions affected by α-synuclein (asyn) pathology, yet how asyn affects these neurons remains unclear. LC-derived norepinephrine (NE) can stimulate neuroprotective mechanisms and modulate immune cells, while dysregulation of NE neurotransmission may exacerbate disease progression, particularly non-motor symptoms, and contribute to the chronic neuroinflammation associated with PD pathology. Although transgenic mice overexpressing asyn have previously been developed, transgene expression is usually driven by pan-neuronal promoters and thus has not been selectively targeted to LC neurons. Here we report a novel transgenic mouse expressing human wild-type asyn under control of the noradrenergic-specific dopamine β-hydroxylase promoter. These mice developed oligomeric and conformation-specific asyn in LC neurons, alterations in hippocampal and LC microglial abundance, upregulated GFAP expression, degeneration of LC fibers, decreased striatal dopamine (DA) metabolism, and age-dependent behaviors reminiscent of non-motor symptoms of PD that were rescued by adrenergic receptor antagonists. These mice provide novel insights into how asyn pathology affects LC neurons and how central noradrenergic dysfunction may contribute to early PD pathophysiology.Significance statementα-synuclein (asyn) pathology and loss of neurons in the locus coeruleus (LC) are two of the most ubiquitous neuropathologic features of Parkinson’s disease (PD). Dysregulated NE neurotransmission is associated with the non-motor symptoms of PD including sleep disturbances, emotional changes such as anxiety and depression, and cognitive decline. Importantly, loss of central NE may contribute to the chronic inflammation in, and progression of, PD. We have generated a novel transgenic mouse expressing human asyn in LC neurons to investigate how increased asyn expression affects the function of the central noradrenergic transmission and associated behaviors. We report cytotoxic effects of oligomeric and conformation-specific asyn, astrogliosis, LC fiber degeneration, disruptions in striatal dopamine metabolism, and age-dependent alterations in non-motor behaviors without inclusions.

scholarly journals Modelling Non-motor Symptoms of Parkinson’s Disease: AAV Mediated Overexpression of Alpha-synuclein in Rat Hippocampus and Basal Ganglia

2020 ◽  
Vol 26 (4) ◽  
pp. 322-329
Author(s):  
Sevgi Uğur Mutluay ◽  
Elif Çınar ◽  
Gül Yalçın Çakmaklı ◽  
Ayşe Ulusoy ◽  
Bülent Elibol ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Basal Ganglia ◽  
Alpha Synuclein ◽  
Rat Hippocampus ◽  
Motor Symptoms ◽  
Non Motor Symptoms

scholarly journals Detection of Phosphorylated Alpha-Synuclein in the Muscularis Propria of the Gastrointestinal Tract Is a Sensitive Predictor for Parkinson’s Disease

2020 ◽  
Vol 2020 ◽  
pp. 1-8 ◽  
Author(s):  
Goichi Beck ◽  
Yumiko Hori ◽  
Yoshito Hayashi ◽  
Eiichi Morii ◽  
Tetsuo Takehara ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Nervous System ◽  
Myenteric Plexus ◽  
Muscularis Propria ◽  
Alpha Synuclein ◽  
Nerve Fibers ◽  
Motor Symptoms ◽  
Submucosal Plexus ◽  
Lewy Pathology

Background. Parkinson’s disease (PD) is a neurodegenerative disorder characterized by motor and nonmotor impairments, including constipation. Lewy bodies and neurites, the pathological hallmarks of PD, are found in the enteric nervous system (ENS) as well as the central nervous system. Constipation is a well-documented premotor symptom in PD, and recent reports have demonstrated Lewy pathology in gastrointestinal (GI) tissues of PD patients prior to the onset of motor symptoms. Objective. In the present study, we assessed Lewy pathology in the GI tracts of seven PD patients who had undergone a gastrectomy, gastric polypectomy, or colonic polypectomy prior to the onset of motor symptoms in order to assess whether the presence of pathological αSyn in the ENS could be a predictor for PD. Methods. GI tissue samples were collected from control patients and patients with premotor PD. Immunohistochemistry was performed using primary antibodies against α-synuclein (αSyn) and phosphorylated αSyn (pαSyn), after which Lewy pathology in each sample was assessed. Results. In all control and premotor PD patients, accumulation of αSyn was observed in the myenteric plexus in both the stomach and colon. In 82% (18/22) of control patients, mild-to-moderate accumulation of αSyn was observed in the submucosal plexus. However, there was no deposition of pαSyn in the ENS of control patients. In patients with premotor PD, abundant accumulation of αSyn was observed in the myenteric plexus, similar to control patients. On the other hand, pαSyn-positive aggregates were also observed in the nerve fibers in the muscularis propria in all examined patients with premotor PD (100%, 3/3), while the deposition of pαSyn in the submucosal plexus was only observed in one patient (14%, 1/7). Conclusion. Our results suggest that the detection of pαSyn, but not αSyn, especially in the muscularis propria of GI tracts, could be a sensitive prodromal biomarker for PD.

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