Focus on the Small GTPase Rab1: A Key Player in the Pathogenesis of Parkinson’s Disease

Parkinson’s disease (PD) is the second most frequent neurodegenerative disease. It is characterized by the loss of dopaminergic neurons in the substantia nigra and the formation of large aggregates in the survival neurons called Lewy bodies, which mainly contain α-synuclein (α-syn). The cause of cell death is not known but could be due to mitochondrial dysfunction, protein homeostasis failure, and alterations in the secretory/endolysosomal/autophagic pathways. Survival nigral neurons overexpress the small GTPase Rab1. This protein is considered a housekeeping Rab that is necessary to support the secretory pathway, the maintenance of the Golgi complex structure, and the regulation of macroautophagy from yeast to humans. It is also involved in signaling, carcinogenesis, and infection for some pathogens. It has been shown that it is directly linked to the pathogenesis of PD and other neurodegenerative diseases. It has a protective effect against α–σψν toxicity and has recently been shown to be a substrate of LRRK2, which is the most common cause of familial PD and the risk of sporadic disease. In this review, we analyze the key aspects of Rab1 function in dopamine neurons and its implications in PD neurodegeneration/restauration. The results of the current and former research support the notion that this GTPase is a good candidate for therapeutic strategies.

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α-Synuclein-induced dysregulation of neuronal activity contributes to murine dopamine neuron vulnerability

npj Parkinson s Disease ◽

10.1038/s41531-021-00210-w ◽

2021 ◽

Vol 7 (1) ◽

Author(s):

Abeer Dagra ◽

Douglas R. Miller ◽

Min Lin ◽

Adithya Gopinath ◽

Fatemeh Shaerzadeh ◽

...

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Neuronal Activity ◽

Dopaminergic Neurons ◽

Prolonged Exposure ◽

D2 Receptor ◽

Neuronal Firing ◽

Dopamine Neurons ◽

Loss Of Function ◽

Therapeutic Implications

AbstractPathophysiological damages and loss of function of dopamine neurons precede their demise and contribute to the early phases of Parkinson’s disease. The presence of aberrant intracellular pathological inclusions of the protein α-synuclein within ventral midbrain dopaminergic neurons is one of the cardinal features of Parkinson’s disease. We employed molecular biology, electrophysiology, and live-cell imaging to investigate how excessive α-synuclein expression alters multiple characteristics of dopaminergic neuronal dynamics and dopamine transmission in cultured dopamine neurons conditionally expressing GCaMP6f. We found that overexpression of α-synuclein in mouse (male and female) dopaminergic neurons altered neuronal firing properties, calcium dynamics, dopamine release, protein expression, and morphology. Moreover, prolonged exposure to the D2 receptor agonist, quinpirole, rescues many of the alterations induced by α-synuclein overexpression. These studies demonstrate that α-synuclein dysregulation of neuronal activity contributes to the vulnerability of dopaminergic neurons and that modulation of D2 receptor activity can ameliorate the pathophysiology. These findings provide mechanistic insights into the insidious changes in dopaminergic neuronal activity and neuronal loss that characterize Parkinson’s disease progression with significant therapeutic implications.

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Loss of SATB1 Induces a p21 Dependent Cellular Senescence Phenotype in Dopaminergic Neurons

10.1101/452243 ◽

2018 ◽

Cited By ~ 1

Author(s):

Markus Riessland ◽

Benjamin Kolisnyk ◽

Tae Wan Kim ◽

Jia Cheng ◽

Jason Ni ◽

...

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Cellular Senescence ◽

Dopaminergic Neurons ◽

Dna Binding Protein ◽

Dopamine Neurons ◽

Human Stem Cell ◽

Transcriptional Program

AbstractCellular senescence is a mechanism used by mitotic cells to prevent uncontrolled cell division. As senescent cells persist in tissues, they cause local inflammation and are harmful to surrounding cells, contributing to aging. Generally, neurodegenerative diseases, such as Parkinson‘s, are disorders of aging. The contribution of cellular senescence to neurodegeneration is still unclear. SATB1 is a DNA binding protein associated with Parkinson’s disease. We report that SATB1 prevents cellular senescence in post-mitotic dopaminergic neurons. Loss of SATB1 causes activation of a cellular senescence transcriptional program in dopamine neurons, both in human stem cell-derived dopaminergic neurons and in mice. We observed phenotypes which are central to cellular senescence in SATB1 knockout dopamine neurons in vitro and in vivo. Moreover, we found that SATB1 directly represses expression of the pro-senescence factor, p21, in dopaminergic neurons. Our data implicate senescence of dopamine neurons as a contributing factor to the pathology of Parkinson’s disease.

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Dysfunction of mitochondria as the basis of Parkinson’s disease

Medical Journal of Cell Biology ◽

10.2478/acb-2018-0027 ◽

2018 ◽

Vol 6 (4) ◽

pp. 174-181

Author(s):

Małgorzata Popis

Keyword(s):

Oxidative Stress ◽

Parkinson’S Disease ◽

Parkinson's Disease ◽

Nervous System ◽

Dopaminergic Neurons ◽

Genetic Factors ◽

Lewy Bodies ◽

Main Ingredient ◽

Mitochondrial Dynamic ◽

Factors Affecting

AbstractParkinson's disease is the second most common neurodegenerative disease, affecting about 0,15-0,3% of the world's population. Its characteristic feature is a loss of dopaminergic neurons in the substantia nigra. PD leads to dopamine deficiency and formation of intracellular inclusions called Lewy bodies, whose main ingredient is α-synuclein. Other types of nervous system cells are also affected by changes associated with that disease. The underlying molecular pathogenesis involves multiple pathways and mechanisms: mitochondrial function, oxidative stress, genetic factors, α-synuclein proteostasis, mitochondrial dynamic impairment, and disorders of the mitophagy process. This review summarizes the factors affecting the functioning of the mitochondria and their connection to the development of Parkinson's disease.

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Presence of genetic polymorphisms may impact on predisposition to Parkinson’s disease

10.5327/1516-3180.004 ◽

2021 ◽

Author(s):

Rubens Barbosa Rezende ◽

Larissa Teodoro

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

High Risk ◽

Dopaminergic Neurons ◽

Lewy Bodies ◽

Single Nucleotide ◽

Asian Populations ◽

Lrrk2 Gene ◽

The Impact ◽

Reduced Risk

Introduction: Parkinson’s disease (PD) is characterized by the degeneration and loss of dopaminergic neurons in the black substantia and the formation of Lewy bodies, thus being considered a neurodegenerative disease. Thus, the objective was to understand the impact of polymorphisms in the predisposition to PD. Methods: It’s a narrative review of literature in the PubMed and SciELO databases, using the descriptors: “Polymorphism, Single Nucleotide” and “Parkinson disease”, registered in DeCS/MeSH, and using the Boolean operator AND. The inclusion criteria were: complete articles and made available free of charge, published in English, Spanish and Portuguese, between 2016 and January 2021. Results: After the research, 167 publications were found and seven were included. The data from the first study indicate that the rs33949390 of the LRRK2 gene helps in predisposition to PD in Asian populations, mainly Chinese. The second study indicated that the NFE2L2 rs6721961 allele was linked to a reduced risk of PD. The third study found that the GSK3B rs1732170, STK11 rs8111699, SNCA rs356219 and FCHSD1 rs456998 polymorphisms were linked to a high risk of PD. The fourth study found that the SNCA variants rs7684318, rs356220, rs356203 and rs2736990 were linked to the disease and were at high risk of developing PD in the Mexican population. The fifth and sixth study are meta-analyzes, the fifth confirming the lower allele rs11558538 of HNMT is associated with a reduced risk of developing PD. And the sixth assumes a possible link between CCDC62 rs12817488 and the risk of PD in the Chinese population. Conclusion: However, the analyzed data indicate that the polymorphisms contributed to the susceptibility to PD, however further studies related to the polymorphisms and their relationship to PD are still needed for more ethnic groups, and thus early diagnosis is possible.

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Interaction between coxsackievirus B3 infection and α-synuclein in models of Parkinson’s disease

PLoS Pathogens ◽

10.1371/journal.ppat.1010018 ◽

2021 ◽

Vol 17 (10) ◽

pp. e1010018

Author(s):

Soo Jin Park ◽

Uram Jin ◽

Sang Myun Park

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Inclusion Body ◽

Dopaminergic Neurons ◽

Inclusion Bodies ◽

Lewy Bodies ◽

Coxsackievirus B3 ◽

Body Formation ◽

Inclusion Body Formation ◽

Cvb3 Infection

Parkinson’s disease (PD) is one of the most common neurodegenerative diseases. PD is pathologically characterized by the death of midbrain dopaminergic neurons and the accumulation of intracellular protein inclusions called Lewy bodies or Lewy neurites. The major component of Lewy bodies is α-synuclein (α-syn). Prion-like propagation of α-syn has emerged as a novel mechanism in the progression of PD. This mechanism has been investigated to reveal factors that initiate Lewy pathology with the aim of preventing further progression of PD. Here, we demonstrate that coxsackievirus B3 (CVB3) infection can induce α-syn-associated inclusion body formation in neurons which might act as a trigger for PD. The inclusion bodies contained clustered organelles, including damaged mitochondria with α-syn fibrils. α-Syn overexpression accelerated inclusion body formation and induced more concentric inclusion bodies. In CVB3-infected mice brains, α-syn aggregates were observed in the cell body of midbrain neurons. Additionally, α-syn overexpression favored CVB3 replication and related cytotoxicity. α-Syn transgenic mice had a low survival rate, enhanced CVB3 replication, and exhibited neuronal cell death, including that of dopaminergic neurons in the substantia nigra. These results may be attributed to distinct autophagy-related pathways engaged by CVB3 and α-syn. This study elucidated the mechanism of Lewy body formation and the pathogenesis of PD associated with CVB3 infection.

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Two Types of Spheroid Bodies in the Nigral Neurons in Parkinson's Disease

Canadian Journal of Neurological Sciences / Journal Canadien des Sciences Neurologiques ◽

10.1017/s0317167100031838 ◽

1991 ◽

Vol 18 (3) ◽

pp. 287-294 ◽

Cited By ~ 17

Author(s):

Tatsuo Yamada ◽

Haruhiko Akiyama ◽

Patrick L. McGeer

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Dopaminergic Neurons ◽

Staining Pattern ◽

Lewy Bodies ◽

Substantia Nigra Pars Compacta ◽

Striatonigral Degeneration ◽

Neurologically Normal ◽

Normal Controls ◽

Dystrophic Dendrites

ABSTRACT:Dendritic spheroid bodies (SBs) and Lewy bodies (LBs) were identified in comparable numbers in the substantia nigra pars compacta (SBC) of nine parkinsonian cases and one case of striatonigral degeneration but were not found irt cases of Huntington's disease or neurologically normal controls. The immunohistochemical profile of the SBs in dystrophic dendrites of nigrostriatal dopaminergic neurons was remarkably similar to that of the LBs found within dendrites or free of the SNC neuropil. Both types of inclusions stained positively with antibodies to tyrosine hydroxylase, ubiquitin and microtubule-associated protein-2 (MAP2), and negatively for Tau-2, although they had different ultrastructural appearances. A few intracellular LBs were stained by antibodies to neurofilament proteins (NFs) 68, 160, and 200 kD, but dendritic SBs and extracellular LBs were not so stained. These data indicate that dendritic SBs and extracellular LBs may have a common molecular pathogenetic origin in Parkinson's disease. On the other hand, the SBs seen in the pars reticulata (SNR) and in the distal nigrostriatal axons even in control cases were generally stained by antibodies to NFs and ubiquitin but not to MAP2. This latter staining pattern in similar to that shown by SBs in the anterior horn in ALS and in the cerebellum of neurologically normal brains and is believed typical of axonal as opposed to dendritic SBs.

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Toxin-Induced and Genetic Animal Models of Parkinson's Disease

Parkinson s Disease ◽

10.4061/2011/951709 ◽

2011 ◽

Vol 2011 ◽

pp. 1-14 ◽

Cited By ~ 11

Author(s):

Shin Hisahara ◽

Shun Shimohama

Keyword(s):

Oxidative Stress ◽

Parkinson’S Disease ◽

Parkinson's Disease ◽

Animal Models ◽

Mitochondrial Dysfunction ◽

Dopaminergic Neurons ◽

Neurodegenerative Disorder ◽

Lewy Bodies ◽

Causative Factors ◽

Genetically Determined

Parkinson's disease (PD) is a common progressive neurodegenerative disorder. The major pathological hallmarks of PD are the selective loss of nigrostriatal dopaminergic neurons and the presence of intraneuronal aggregates termed Lewy bodies (LBs), but the pathophysiological mechanisms are not fully understood. Epidemiologically, environmental neurotoxins such as pesticides are promising candidates for causative factors of PD. Oxidative stress and mitochondrial dysfunction induced by these toxins could contribute to the progression of PD. While most cases of PD are sporadic, specific mutations in genes that cause familial forms of PD have led to provide new insights into its pathogenesis. This paper focuses on animal models of both toxin-induced and genetically determined PD that have provided significant insight for understanding this disease. We also discuss the validity, benefits, and limitations of representative models.

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Dopamine D2 Long Receptors Are Critical for Caveolae-Mediated α-Synuclein Uptake in Cultured Dopaminergic Neurons

Biomedicines ◽

10.3390/biomedicines9010049 ◽

2021 ◽

Vol 9 (1) ◽

pp. 49

Author(s):

Ichiro Kawahata ◽

Tomoki Sekimori ◽

Haoyang Wang ◽

Yanyan Wang ◽

Toshikuni Sasaoka ◽

...

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Dopaminergic Neurons ◽

Dopamine D2 Receptor ◽

D2 Receptor ◽

Dopamine Neurons ◽

Fatty Acid Binding ◽

Caveolin 1 ◽

Dopamine D2 ◽

C Terminus

α-synuclein accumulation into dopaminergic neurons is a pathological hallmark of Parkinson’s disease. We previously demonstrated that fatty acid-binding protein 3 (FABP3) is critical for α-synuclein uptake and propagation to accumulate in dopaminergic neurons. FABP3 is abundant in dopaminergic neurons and interacts with dopamine D2 receptors, specifically the long type (D2L). Here, we investigated the importance of dopamine D2L receptors in the uptake of α-synuclein monomers and their fibrils. We employed mesencephalic neurons derived from dopamine D2L−/−, dopamine D2 receptor null (D2 null), FABP3−/−, and wild type C57BL6 mice, and analyzed the uptake ability of fluorescence-conjugated α-synuclein monomers and fibrils. We found that D2L receptors are co-localized with FABP3. Immunocytochemistry revealed that TH+ D2L−/− or D2 null neurons do not take up α-synuclein monomers. The deletion of α-synuclein C-terminus completely abolished the uptake to dopamine neurons. Likewise, dynasore, a dynamin inhibitor, and caveolin-1 knockdown also abolished the uptake. D2L and FABP3 were also critical for α-synuclein fibrils uptake. D2L and accumulated α-synuclein fibrils were well co-localized. These data indicate that dopamine D2L with a caveola structure coupled with FABP3 is critical for α-synuclein uptake by dopaminergic neurons, suggesting a novel pathogenic mechanism of synucleinopathies, including Parkinson’s disease.

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

Neurodegenerative Diseases ◽

10.1159/000511083 ◽

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

Background: 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. Summary: Cumulative evidence implicates that abnormal processing of α-syn will be predicted to lead to pathological changes in PD. Key Messages: 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.

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Alpha synuclein aggresomes inhibit ciliogenesis and multiple functions of the centrosome

10.1101/2019.12.20.884643 ◽

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.

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