Integrins—A missing link in synuclein's pathogenic mechanism

Surguchev, Alexei; Surguchov, Andrei

doi:10.1002/jnr.24384

Cited by 5 publications

(4 citation statements)

References 31 publications

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“…Several lines of research have focused on the interactions between the ECM and extracellular alpha synuclein based on evidence that alpha synuclein can be secreted from cells via exosomes in an activity-dependent manner [ 82 , 83 ]. One area of investigation is the identification of mechanisms by which alpha synuclein activates microglia, initiating a proinflammatory response characterized by elevated cytokine production [ 84 , 85 ]. At least one of the receptors involved in microglial activation is the integrin CD11b (the alpha chain of integrin αMβ2); alpha synuclein binding to integrin CD11b activates microglial NADPH oxidase (NOX2) through a RhoA-dependent pathway, a potential mechanism by which extracellular alpha synuclein could cause neuronal damage and death [ 86 ].…”

Section: Discussionmentioning

confidence: 99%

A Systematic Review of Extracellular Matrix-Related Alterations in Parkinson’s Disease

Chapman,

Sorg

2024

Brain Sciences

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The role of the extracellular matrix (ECM) in Parkinson’s disease (PD) is not well understood, even though it is critical for neuronal structure and signaling. This systematic review identified the top deregulated ECM-related pathways in studies that used gene set enrichment analyses (GSEA) to document transcriptomic, proteomic, or genomic alterations in PD. PubMed and Google scholar were searched for transcriptomics, proteomics, or genomics studies that employed GSEA on data from PD tissues or cells and reported ECM-related pathways among the top-10 most enriched versus controls. Twenty-seven studies were included, two of which used multiple omics analyses. Transcriptomics and proteomics studies were conducted on a variety of tissue and cell types. Of the 17 transcriptomics studies (16 data sets), 13 identified one or more adhesion pathways in the top-10 deregulated gene sets or pathways, primarily related to cell adhesion and focal adhesion. Among the 8 proteomics studies, 5 identified altered overarching ECM gene sets or pathways among the top 10. Among the 4 genomics studies, 3 identified focal adhesion pathways among the top 10. The findings summarized here suggest that ECM organization/structure and cell adhesion (particularly focal adhesion) are altered in PD and should be the focus of future studies.

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Section: Discussionmentioning

confidence: 99%

A Systematic Review of Extracellular Matrix-Related Alterations in Parkinson’s Disease

Chapman,

Sorg

2024

Brain Sciences

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“…Elevated levels of α-syn protein in the muscle and other regions can enter the brain and induce the pathological process of PD [ 20 ]. Therefore, we suggest that increased α-syn levels induced by decreased ITGA7 levels may accelerate the pathological process of PD [ 21 , 22 ]. Consistent with a previous study examining changes in brain ITGA7 expression, the results of the present study also revealed that decreased ITGA7 expression could induce increased α-syn expression in the muscle.…”

Section: Discussionmentioning

confidence: 99%

Association between Decreased ITGA7 Levels and Increased Muscle α-Synuclein in an MPTP-Induced Mouse Model of Parkinson’s Disease

Han

Lim

2022

IJMS

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Parkinson's disease (PD) is a neurodegenerative disease characterized by the loss of dopaminergic neurons in the substantia nigra (SN), reducing dopaminergic levels in the striatum and affecting motor control. Herein, we investigated the potential relationship between integrin α7 (ITGA7) and α-synuclein (α-syn) in the muscle of methyl-4-phenyl-1,2,3,6 tetrahydropyridine (MPTP)-induced mice and C2C12 cells. To characterize the pathology of PD, we examined the expression of tyrosine hydroxylase (TH) in the SN of the midbrain. Compared with the control group, MPTP-treated mice showed a significant decrease in TH expression in the SN, accompanied by a significant decrease in muscle ITGA7 expression. Compared with the control group, α-syn expression was increased in the MPTP group. Furthermore, the pattern of α-syn expression in the MPTP group was similar to the ITGA7 expression pattern in the control group (linear forms). To determine the relationship between ITGA7 and PD, we examined the expression of ITGA7 and α-syn after ITGA7 knockdown using siRNA in C2C12 cells. ITGA7 expression significantly decreased while α-syn expression significantly increased in siRNA-treated C2C12 cells. These results suggest that decreased ITGA7 muscle expression could increase α-syn expression. Moreover, α-syn accumulation, induced by decreased muscle ITGA7, might contribute to PD pathology.

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“…In addition, ITGA7 deficiency is common in muscular dystrophy and myopathy [ 14 ]. α-syn and integrin were first reported in 2005, in a case of MSA, another synucleinopathy [ 15 ], and there are also recent studies reporting integrins and α-syn [ 16 , 17 ].…”

Section: Introductionmentioning

confidence: 99%

Decrease in ITGA7 Levels Is Associated with an Increase in α-Synuclein Levels in an MPTP-Induced Parkinson’s Disease Mouse Model and SH-SY5Y Cells

Han

Seo

Lim

2021

IJMS

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We investigated the potential association between integrin α7 (ITGA7) and alpha-synuclein (α-syn) in a methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced Parkinson’s disease (PD) mouse model. Tyrosine hydroxylase (TH), ITGA7, and α-syn expression in the substantia nigra (SN) of the brain were observed to examine the pathological characteristics of PD. To determine the relationship between ITGA7 and PD, the expression of TH and α-syn was investigated after ITGA7 siRNA knockdown in SH-SY5Y cells. The ITGA7 microarray signal was decreased in the SN of the MPTP group, indicating reduced ITGA7 expression compared to that in the control. The expression patterns of ITGA7 in the control group and those of α-syn in the MPTP group were similar on immunohistochemical staining. Reduction in ITGA7 expression by ITGA7 siRNA administration induced a decrease in TH expression and an increase in α-syn expression in SH-SY5Y cells. The decreased expression of ITGA7 significantly decreased the expression of bcl2 and increased the bax/bcl2 ratio in SH-SY5Y cells. These results suggest that reduced ITGA7 expression may be related to increased α-syn expression and apoptosis of dopaminergic cells in an MPTP-induced PD mouse model. To the best of our knowledge, this is the first study to show an association between ITGA7 and PD.

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Integrins—A missing link in synuclein's pathogenic mechanism

Cited by 5 publications

References 31 publications

A Systematic Review of Extracellular Matrix-Related Alterations in Parkinson’s Disease

A Systematic Review of Extracellular Matrix-Related Alterations in Parkinson’s Disease

Association between Decreased ITGA7 Levels and Increased Muscle α-Synuclein in an MPTP-Induced Mouse Model of Parkinson’s Disease

Decrease in ITGA7 Levels Is Associated with an Increase in α-Synuclein Levels in an MPTP-Induced Parkinson’s Disease Mouse Model and SH-SY5Y Cells

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