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 cellular functions and may result in disease. However, 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 in disease pathogenesis. Thus, due to the ECM's diversified biological roles, increasing interest in its involvement in disease, and the lack of sufficient compiled evidence regarding its relationship with Parkinson's disease (PD) pathology, we aimed to compile the existing evidence to boost the current knowledge on the area and provide refined guidance for the future research. 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). A literature search was conducted up until 10 February 2023. The overall hits from the database and manual search for proteomic and transcriptome studies were 1243 and 1041 articles, respectively. Following a full-text review, 10 articles from proteomic and 24 from transcriptomic studies were found to be eligible for inclusion. 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. A limited number of relevant studies were accessed from our search, indicating that much work remains to be carried out 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.

Keywords: Parkinson’s disease; extracellular matrix; induced pluripotent stem cells; post mortem tissue; proteins; transcription.

Figure 1

Preferred reporting items for systematic reviews and meta analyses (PRISMA) flow diagram of the search strategy.

Figure 2

The percentage of PD patients (“case”) and controls from the included proteomic and transcriptomic studies.

Figure 3

Distribution of patient- and sample-related variables of both proteomic and transcriptomic studies. Distribution of PD type (A); age distribution (B); PMI distribution of brain tissue-based studies (C).

Figure 4

Summary of data from both proteomic and transcriptomic studies. The origin of the included articles (A); brain region from which the samples were taken for transcriptomic studies (B); methods applied for transcriptomic analysis (C); percentage of ECM-related differentially expressed proteins per brain region (D) (SN: substantia nigra; FC: frontal cortex; LC: locus ceruleus; OB: olfactory bulbs; FL: frontal lobe; PC: posterior cingulate cortex; DEP: differentially expressed protein).

Figure 4

Summary of data from both proteomic and transcriptomic studies. The origin of the included articles (A); brain region from which the samples were taken for transcriptomic studies (B); methods applied for transcriptomic analysis (C); percentage of ECM-related differentially expressed proteins per brain region (D) (SN: substantia nigra; FC: frontal cortex; LC: locus ceruleus; OB: olfactory bulbs; FL: frontal lobe; PC: posterior cingulate cortex; DEP: differentially expressed protein).

Figure 5

Frequency of commonly reported (reported from, at least, two of the included studies) differentially expressed proteins from postmortem tissue of PD patients compared with healthy controls.

Figure 6

Commonly reported pathways/processes/groups of genes from postmortem and iPSC-based studies (Cell–cell /cell–matrix = ECM–receptor interaction, cell–matrix interaction, focal adhesion, cell adhesion molecules and cell adhesion).

Figure 7

A diagram showing the main findings from all studies included in the review (the color of the study type is matched with the listed main finding; the gray background is for postmortem brain tissue-based studies and the white background is for iPSC-based studies, orange color for transcriptomic studies with related findings and light green for proteomic studies with related findings).