Multi‐omic landscaping of human midbrains identifies disease‐relevant molecular targets and pathways in advanced‐stage Parkinson's disease

Abstract

Background Parkinson's disease (PD) is the second most common neurodegenerative disorder whose prevalence is rapidly increasing worldwide. The molecular mechanisms underpinning the pathophysiology of sporadic PD remain incompletely understood. Therefore, causative therapies are still elusive. To obtain a more integrative view of disease‐mediated alterations, we investigated the molecular landscape of PD in human post‐mortem midbrains, a region that is highly affected during the disease process. Methods Tissue from 19 PD patients and 12 controls were obtained from the Parkinson's UK Brain Bank and subjected to multi‐omic analyses: small and total RNA sequencing was performed on an Illumina's HiSeq4000, while proteomics experiments were performed in a hybrid triple quadrupole‐time of flight mass spectrometer (TripleTOF5600+) following quantitative sequential window acquisition of all theoretical mass spectra. Differential expression analyses were performed with customized frameworks based on DESeq2 (for RNA sequencing) and with Perseus v.1.5.6.0 (for proteomics). Custom pipelines in R were used for integrative studies. Results Our analyses revealed multiple deregulated molecular targets linked to known disease mechanisms in PD as well as to novel processes. We have identified and experimentally validated (quantitative real‐time polymerase chain reaction/western blotting) several PD‐deregulated molecular candidates, including miR‐539‐3p, miR‐376a‐5p, miR‐218‐5p and miR‐369‐3p, the valid miRNA‐mRNA interacting pairs miR‐218‐5p/RAB6C and miR‐369‐3p/GTF2H3, as well as multiple proteins, such as CHI3L1, HSPA1B, FNIP2 and TH. Vertical integration of multi‐omic analyses allowed validating disease‐mediated alterations across different molecular layers. Next to the identification of individual molecular targets in all explored omics layers, functional annotation of differentially expressed molecules showed an enrichment of pathways related to neuroinflammation, mitochondrial dysfunction and defects in synaptic function. Conclusions This comprehensive assessment of PD‐affected and control human midbrains revealed multiple molecular targets and networks that are relevant to the disease mechanism of advanced PD. The integrative analyses of multiple omics layers underscore the importance of neuroinflammation, immune response activation, mitochondrial and synaptic dysfunction as putative therapeutic targets for advanced PD.

Transcriptomic signatures responding to PKM2 activator TEPP-46 in the hyperglycemic human renal proximal epithelial tubular cells

“…HSPA8 was involved in AQP2 internalization; coordinately, HSPA1B was likely to play a role in AQP2 trafficking to the apical plasma membrane ( 48 ). HSPA1B had been identified as one disease-relevant molecular target in advanced-stage Parkinson’s disease ( 49 ). Upregulated HSPA2 exerted a neuroprotective effect through its regulation of endocytosis in a rat middle cerebral artery occlusion model ( 50 ), and inhibition of HSPA8 would protect against spinal ischemia–reperfusion injury via astrocyte NF-κB/NLRP3 inflammasome pathway ( 51 ).…”

Proteomic analysis of the human hippocampus identifies neuronal pentraxin 1 (NPTX1) as synapto‐axonal target in late‐stage Parkinson's disease

“…Table S1 summarizes clinical information about the subjects. Punch biopsies were taken for whole tissue lysates (WTL) as previously described in Caldi Gomes et al (2022) with few adaptations (detailed in the Supporting Information methods section). For synaptosomal fractions (SF), samples from six PD patients and four CTR were used.…”

“…WTL samples were subjected to DIA-MS as described in Caldi Gomes et al (2022) with few adaptations. More details about the experimental setup for DIA-MS runs are described in the Supporting Information methods.…”

Parkinson’s disease therapy: what lies ahead?

“…A pro-inflammatory immune phenotype, characterized by innate and adaptive immune cell activation, increase of circulating pro-inflammatory cytokines, blood–brain barrier permeability and peripheral immune cell infiltration of the central nervous system has been identified as hallmark of PD. Immunomodulatory or anti-inflammatory approaches may therefore represent promising disease-modifying targets (Tansey et al 2022 ; Caldi Gomes et al 2022 ). Some anti-inflammatory efforts have failed to provide satisfactory efficacy to date (e.g., NSAIDs (Poly et al 2019 ), simvastatin (Stevens et al 2022 ), verdiperstat (Biohaven Pharmaceutical Holding Company Ltd. 2021 )).…”