Upregulated extracellular matrix-related genes and impaired synaptic activity in dopaminergic and hippocampal neurons derived from Parkinson’s disease patients withPINK1andPARK2mutations

Abstract

Parkinson's disease (PD) is the second most prevalent neurodegenerative disease. Primary symptoms of PD arise with the loss of dopaminergic (DA) neurons in the Substantia Nigra Pars Compacta, but it affects the hippocampus and cortex also, usually in its later stage. Approximately 15% of PD cases familial with a genetic mutation. Two of the most associated genes with autosomal recessive (AR) early-onset familial PD are PINK1 and PARK2. There is a need for In-vitro studies of these genetic mutations in order to understand the neurophysiological changes in patients' neurons that may contribute to neurodegeneration. In this work, we generated and differentiated DA and hippocampal neurons from iPSCs derived from two patients with a double mutation in their PINK1 and PARK2 (one homozygous and one heterozygous) genes and assessed their neurophysiology compared to two healthy controls. We showed that the synaptic activity of PD neurons generated from patients with the PINK1 and PARK2 mutations is impaired in the hippocampus and dopaminergic neurons. Mutant dopaminergic neurons had enhanced excitatory post-synaptic activity. In addition, DA neurons with the homozygous mutation of PINK1 exhibited more pronounced electrophysiological differences compared to the control neurons. Signaling network analysis of RNA sequencing results revealed that Focal adhesion and ECM receptor pathway were the top 2 upregulated pathways in the mutant PD neurons. These phenotypes are reversed to PD phenotypes of other mutations, suggesting that the interaction of the two mutations may yield different mechanisms of PD.

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

“…In this study, we concentrated on the neurophysiology and transcriptional alterations in DA neurons derived from PD patients with GBA1 mutations and sPD patients. Our results revealed distinct and shared dysregulated pathways in both GBA1-associated and sPD cases, some that are shared with our previous reports for other mutations (26,27,67). In GBA1-associated PD, we found a significantly reduced influx of sodium currents and hypo excitability in DA neurons as well as dysregulation in ECM-receptor interactions, focal adhesion, and more pathways.…”

“…Similar results were obtained from a twin study that looked at iPSC-derived DA neurons and discovered that GBA1 mutations are connected to an elevated α-synuclein and impaired GCase activity (66). As reviewed by Tran et al (57), though sPD accounts for a significant portion of all cases of PD, there are not many iPSC studies of sPD (26,27,67).…”

“…Pathologically, sPD is often characterized by the accumulation of αsynuclein in Lewy bodies and the degeneration of DA neurons in the substantia nigra pars compacta (25). Recent studies on sPD cases have demonstrated alterations in synaptic activity and dysregulated extracellular matrix pathways in midbrain neurons derived from PD patients (26,27).…”

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

“…in their recent study on sporadic PD patients, reported a possible connection between the COL6A3 gene variants and susceptibility to PD. According to our proteomic review work, collagens IV and VI were found to be upregulated in PD patients (79,80,89) although transcriptomic studies showed a dysregulation of Collagen IV in both directions (15,16). Along with other studies from different PD models, our review work highlights the functional role of collagen (especially Collagen VI) in neuronal cells and their neuroprotective potential against neurodegeneration (119).…”

“…In order to stabilize the ECM at the cell surface, fibronectin need uninterrupted polymerization into fibrils, which in turn requires adequate delivery of integrins (129,130). In our literature review the integrin gene expression was upregulated in both postmortem and iPSC-based studies PD patients (15,16) and opposite expression between fibronectin and integrin was also reported in iPSC based studies (15,16). Such contradicting results from co-functioning genes necessitate further work to figure out their exact contribution in PD pathogenesis.…”