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.

Gene Expression Profiling of Post Mortem Midbrain of Parkinson’s Disease Patients and Healthy Controls

“…Referring to the review by Rike and Stern [43], our study, at the pathway analysis level, reveals some overlaps with interaction mechanisms and cell adhesion molecules. Importantly, we have identified data that were not previously highlighted in the literature.…”

“…The review by Rike and Stern [43] cites proteomic and transcriptomic studies involving post mortem brain samples from individuals with PD compared to controls. Some authors of these studies concentrated on the transcriptome in the substantia nigra [44,45].…”

Synaptic dysfunction and extracellular matrix dysregulation in dopaminergic neurons from sporadic and E326K-GBA1 Parkinson’s disease patients

“…These findings suggest a focus on the ECM and its strong involvement in PD. Studies of the ECM composition and structure should be conducted as these are currently under-explored in PD 73 , 74 . The brain ECM has been shown to closely affect neurite outgrowth and connectivity during neural development 75 .…”

Leveraging Biomaterial Platforms to Study Aging-Related Neural and Muscular Degeneration

“…As for Parkinson's, the main histological manifestations of this disease include the formation of fibrillar aggregates of α-synuclein, known as Lewy bodies, and the loss of dopaminergic neurons in the substantia nigra [12] (Figure 1). Symptoms develop when 70-80% of dopaminergic neurons have been degraded, and include bradykinesia, resting tremors, and increased muscular rigidity [13,14].…”

“…degraded, and include bradykinesia, resting tremors, and increased muscular rigidity [13,14]. Aging-related nerve cell degeneration can also result in the loss of muscle mass and function.…”