Tackling the Biological Meaning of the Human Olfactory Bulb Dyshomeostatic Proteome across Neurological Disorders: An Integrative Bioinformatic Approach

Abstract

Olfactory dysfunction is considered an early prodromal marker of many neurodegenerative diseases. Neuropathological changes and aberrant protein aggregates occur in the olfactory bulb (OB), triggering a tangled cascade of molecular events that is not completely understood across neurological disorders. This study aims to analyze commonalities and differences in the olfactory protein homeostasis across neurological backgrounds with different spectrums of smell dysfunction. For that, an integrative analysis was performed using OB proteomics datasets derived from subjects with Alzheimer’s disease (AD), Parkinson´s disease (PD), mixed dementia (mixD), dementia with Lewy bodies (DLB), frontotemporal lobar degeneration (FTLD-TDP43), progressive supranuclear palsy (PSP) and amyotrophic lateral sclerosis (ALS) with respect to OB proteome data from neurologically intact controls. A total of 80% of the differential expressed protein products were potentially disease-specific whereas the remaining 20% were commonly altered across two, three or four neurological phenotypes. A multi-level bioinformatic characterization revealed a subset of potential disease-specific transcription factors responsible for the downstream effects detected at the proteome level as well as specific densely connected protein complexes targeted by several neurological phenotypes. Interestingly, common or unique pathways and biofunctions were also identified, providing novel mechanistic clues about each neurological disease at olfactory level. The analysis of olfactory epithelium, olfactory tract and primary olfactory cortical proteotypes in a multi-disease format will functionally complement the OB dyshomeostasis, increasing our knowledge about the neurodegenerative process across the olfactory axis.

Proteoform Analysis of the Human Olfactory System: A Window into Neurodegenerative Diseases

“…They identified that the purine nucleoside phosphorylase (PNP) was the only over-expressed protein in AD, PD, MixD, and ALS. Thirteen OB proteins were differentially regulated in at least three neurological disorders, of which four of them (NCAM2, LY6H, COL6A3, and PRDX6) presented a homogeneous OB profile across diseases [ 41 ]. In addition, the epidermal growth factor receptor (EGFR) expression was significantly increased in the OB of AD and mixed dementia subjects [ 42 ].…”

“…Still, it remains unclear which biochemical alterations cause the olfactory dysfunction in AD. Some authors propose SREBF1 and NFMUE1 (involving genes with 3′UTR containing motif CGGCCATCT) as transcription factors with a specific role of mediators relevant in AD olfactory neurodegeneration [ 41 ].…”

“…In the FTLD-TDP43, there was a specific phosphoinositide-dependent protein kinase 1 (PDK1) inactivation [ 49 ]. Another finding on FTLD-TDP43 patients is the specific enrichment of proteins regulated by NMYC [ 41 ].…”

“…Also, network-driven proteomics revealed a modulation in ERK1/2, MKK3/6, and PDK1/PKC signaling axes [ 51 ]. At the transcriptional level, bioinformatics analysis predicted HDAC1, CIITA, MYC, CDC5L, USF, and PTF1β as potential regulators of the OB-modulated proteome in PD cases [ 41 ].…”

“…In MixD the proteomic analysis revealed that Nuclear Factor I/C was the only transcription factor potentially involved in OB proteoform imbalance in this neurological disease. Enrichment analysis pointed out that proteoglycans, ADP-ribosylation factor 3 (ARF3) pathway, NOVA-regulated synaptic proteins, NOTCH3 signaling, synthesis of GPI-anchored proteins, glutathione conjugation and phosphatidylinositol signaling were part of the pathways selectively enhanced in MixD cases [ 41 ].…”