Proteins and transcriptional dysregulation of the brain extracellular matrix in Parkinson’s disease: A systematic review

Abstract

The extracellular matrix (ECM) of the brain is a dynamic structure made up of a vast network of bioactive macromolecules that modulate cellular events. Structural, organizational and functional changes in these macromolecules due to genetic variation or environmental stressors are thought to affect the cellular functions, and may result in disease. Most mechanistic studies to date usually focus on the cellular aspects of diseases and pay less attention to the relevance of the processes governing the dynamic nature of the extracellular matrix on disease pathogenesis. Here in this review, we gathered postmortem brain tissue and induced pluripotent stem cell (iPSC)-related studies from PubMed and Google scholar to identify, summarize and describe common macromolecular alterations in the expression of brain ECM components in Parkinson’s disease (PD). According to proteomic studies, proteins such as collagens, fibronectin, annexins and tenascins were recognized to be differentially expressed in Parkinson’s disease. Transcriptomic studies displayed dysregulated pathways including ECM-receptor interaction, focal adhesion, and cell adhesion molecules in Parkinson’s disease. Limited number of relevant studies were accessed from our search indicating that much work still remains to be done to better understand the roles of the ECM in neurodegeneration and Parkinson’s disease. However, we believe that our review will elicit focused primary studies and thus, support the ongoing efforts of the discovery and development of diagnostic biomarkers as well as therapeutic agents for Parkinson’s disease.

Synaptic dysfunction and dysregulation of extracellular matrix-related genes in dopaminergic neurons derived from Parkinson’s disease sporadic patients and withGBA1mutations

“…Transcriptome analysis and comparison between PD and control DA neurons indicate several intracellular and extracellular pathways that are dysregulated in PD. These include focal adhesion and ECM-receptor interaction which are commonly dysregulated in PD in this study and previous studies (26,27,79). These findings suggest a focus on the ECM and its strong involvement in PD.…”

“…This finding is consistent with several studies using PD model mice, which suggested that the early phenotype is a decrease in synaptic activity that progressed to motor dysfunction inmany later stages. Thus, monitoring synaptic activity may have a significant impact on the early diagnosis and prediction of PD onset (76)(77)(78)(79)(80).…”

Brain Extracellular Matrix implications in multiple neurological disorders are revealed through a meta-analysis of transcriptional changes

“…Many pathways related to the brain ECM were dysregulated in all the neurological disorders that were considered. The ECM has emerged as a central focus in neuroscience [83, 84], recognized as an integral part of neural functions, especially synaptic regulation [85] [86]. Dityatev et al introduced the concept of the ’tetra-partite synapse’ that expands the traditional understanding of synaptic structure and function.…”

Early maturation and hyperexcitability is a shared phenotype of cortical neurons derived from different ASD-associated mutations

“…and other neurodegenerative diseases such as Parkinson's [93][94][95][96] and schizophrenia [97][98][99]. Here we concentrated on the early developmental physiological alterations in 4 different ASD and epilepsy-related genes.…”