Endothelial Degeneration of Parkinson's Disease is Related to Alpha-Synuclein Aggregation

Yang, Panzao; Min, Xiaoli; Mohammadi, Mojdeh; Turner, Clinton; Faull, Richard L. M.; Waldvogel, Henry J.; Dragunow, Mike; Guan, Jian

doi:10.4172/2161-0460.1000370

Cited by 17 publications

(14 citation statements)

References 28 publications

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“…The average size of p62 bodies was larger in PD patients compared to control ( p < 0.05), implicating the accumulation of p62 or impairment of autophagy in PD being linked to Lewy body formation. 191…”

Section: Genetic Regulation Of P62/sqstm1 In Neurodegenerative Diseasesmentioning

confidence: 99%

SQSTM1/p62: A Potential Target for Neurodegenerative Disease

Attarwala

Xie³

2019

ACS Chem. Neurosci.

131

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Neurodegenerative diseases, characterized by a progressive loss of brain function, affect the lives of millions of individuals worldwide. The complexity of the brain poses a challenge for scientists trying to map the biochemical and physiological pathways to identify areas of pathological errors. Brain samples of patients with neurodegenerative diseases have been shown to contain large amounts of misfolded and abnormally aggregated proteins, resulting in dysfunction in certain brain centers. Removal of these abnormal molecules is essential in maintaining protein homeostasis and overall neuronal health. Macroautophagy is a major route by which cells achieve this. Administration of certain autophagy-enhancing compounds has been shown to provide therapeutic effects for individuals with neurodegenerative conditions. SQSTM1/p62 is a scaffold protein closely involved in the macroautophagy process. p62 functions to anchor the ubiquitinated proteins to the autophagosome membrane, promoting degradation of unwanted molecules. Modulators targeting p62 to induce autophagy and promote its protective pathways for aggregate protein clearance have high potential in the treatment of these conditions. Additionally, causal relationships have been found between errors in regulation of SQSTM1/p62 and the development of a variety of neurodegenerative disorders, including Alzheimer’s, Parkinson’s, Huntington’s, amyotrophic lateral sclerosis, and frontotemporal lobar degeneration. Furthermore, SQSTM1/p62 also serves as a signaling hub for multiple pathways associated with neurodegeneration, providing a potential therapeutic target in the treatment of neurodegenerative diseases. However, rational design of a p62-oriented autophagy modulator that can balance the negative and positive functions of multiple domains in p62 requires further efforts in the exploration of the protein structure and pathological basis.

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Section: Genetic Regulation Of P62/sqstm1 In Neurodegenerative Diseasesmentioning

confidence: 99%

SQSTM1/p62: A Potential Target for Neurodegenerative Disease

Attarwala

Xie³

2019

ACS Chem. Neurosci.

131

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Section: Introductionmentioning

confidence: 99%

“…Studies have also found pathological alteration of endothelial cells lining the cerebral blood vessels in PD [ 9 , 10 ]. Brain endothelial degeneration with surrounding α-synuclein pathologies has been seen in postmortem brain tissues in PD [ 10 ]. Moreover, in a previous study, α-synuclein PFF treatment of cultured cerebral endothelial cells led to altered expression of tight junction proteins [ 11 ], suggesting a pathological role of α-synuclein pathology in endothelial function.…”

Section: Introductionmentioning

confidence: 99%

Brain Endothelial P-Glycoprotein Level Is Reduced in Parkinson’s Disease via a Vitamin D Receptor-Dependent Pathway

Kim

Shin

Lee

et al. 2020

IJMS

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The progressive neurodegeneration in Parkinson’s disease (PD) is accompanied by neuroinflammation and endothelial vascular impairment. Although the vitamin D receptor (VDR) is expressed in both dopamine neurons and brain endothelial cells, its role in the regulation of endothelial biology has not been explored in the context of PD. In a 6-hydroxydopamine (6-OHDA)-induced PD mouse model, we observed reduced transcription of the VDR and its downstream target genes, CYP24 and MDR1a. The 6-OHDA-induced transcriptional repression of these genes were recovered after the VDR ligand—1α,25-dihydroxyvitamin D3 (1,25(OH)2D3) treatment. Similarly, reduced vascular protein expression of P-glycoprotein (P-gp), encoded by MDR1a, after 6-OHDA administration was reversed by 1,25(OH)2D3. Moreover, marked reduction of endothelial P-gp expression with concomitant α-synuclein aggregation was found in a combinatorial AAV-αSyn/αSyn preformed fibril (PFF) injection mouse model and postmortem PD brains. Supporting the direct effect of α-synuclein aggregation on endothelial biology, PFF treatment of human umbilical vein endothelial cells (HUVECs) was sufficient to induce α-synuclein aggregation and repress transcription of the VDR. PFF-induced P-gp downregulation and impaired functional activity in HUVECs completely recovered after 1,25(OH)2D3 treatment. Taken together, our results suggest that a dysfunctional VDR-P-gp pathway could be a potential target for the maintenance of vascular homeostasis in PD pathological conditions.

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“…At the systems level, the determinants that might contribute to differential PD phenotypes are excitotoxicity 3 , 105 (due to overexcitation by STN or pedunculopontine nucleus), aging 106 , 107 (due to proteostatic dysfunction, mitochondrial dysfunction, genetic mutations or telomere shortening), genetic instability 108 – 110 (due to changes in nucleic acid sequences, chromosomal rearrangements or aneuploidy), environmental toxins 111 , 112 (due to exposure to insecticides, commercial solvents, metal exposure or traumatic head injury), neuroinflammation 113 , 114 (due to traumatic head injury, exotoxins or immune dysfunctions), prion-like infection 114 , 115 (bacteria or viruses), telomere shortening 116 , 117 (due to aging or oxidative stress), glial dysfunction 118 – 120 (due to phagocytic or inflammatory impairments, enteric glial dysfunction) and vascular dysfunction 121 , 122 (due to endothelial dysfunction or cardiovascular autonomic dysfunction). These systems-level determinants interact among themselves and also across different levels in the hierarchy resulting in different PD phenotypes (Fig.…”

Section: Discussionmentioning

confidence: 99%

Influence of energy deficiency on the subcellular processes of Substantia Nigra Pars Compacta cell for understanding Parkinsonian neurodegeneration

Muddapu

Chakravarthy

2021

Sci Rep

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Parkinson’s disease (PD) is the second most prominent neurodegenerative disease around the world. Although it is known that PD is caused by the loss of dopaminergic cells in substantia nigra pars compacta (SNc), the decisive cause of this inexorable cell loss is not clearly elucidated. We hypothesize that “Energy deficiency at a sub-cellular/cellular/systems level can be a common underlying cause for SNc cell loss in PD.” Here, we propose a comprehensive computational model of SNc cell, which helps us to understand the pathophysiology of neurodegeneration at the subcellular level in PD. The aim of the study is to see how deficits in the supply of energy substrates (glucose and oxygen) lead to a deficit in adenosine triphosphate (ATP). The study also aims to show that deficits in ATP are the common factor underlying the molecular-level pathological changes, including alpha-synuclein aggregation, reactive oxygen species formation, calcium elevation, and dopamine dysfunction. The model suggests that hypoglycemia plays a more crucial role in leading to ATP deficits than hypoxia. We believe that the proposed model provides an integrated modeling framework to understand the neurodegenerative processes underlying PD.

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Endothelial Degeneration of Parkinson's Disease is Related to Alpha-Synuclein Aggregation

Cited by 17 publications

References 28 publications

SQSTM1/p62: A Potential Target for Neurodegenerative Disease

SQSTM1/p62: A Potential Target for Neurodegenerative Disease

Brain Endothelial P-Glycoprotein Level Is Reduced in Parkinson’s Disease via a Vitamin D Receptor-Dependent Pathway

Influence of energy deficiency on the subcellular processes of Substantia Nigra Pars Compacta cell for understanding Parkinsonian neurodegeneration

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