Unveiling the olfactory proteostatic dissangement in Parkinson's disease by proteome-wide profiling

Abstract

Olfactory dysfunction is one of the earliest features in Lewy-type alphasynucleinopathies (LTS) such as Parkinson´s disease (PD). However, the underlying molecular mechanisms associated to smell impairment are poorly understood. Applying mass spectrometry-based quantitative proteomics in postmortem olfactory bulbs (OB) across limbic, early-neocortical, and neocortical LTS stages of parkinsonian subjects, a proteostasis impairment was observed, identifying 268 differentially expressed proteins between controls and PD phenotypes. In addition, network-driven proteomics revealed a modulation in ERK1/2, MKK3/6, and PDK1/PKC signalling axis. Moreover, a crossdisease study of selected olfactory molecules in sporadic Alzheimer's disease (AD) cases, revealed different protein derangements in the modulation of Secretagogin (SCGN), Calcyclin binding protein (CACYBP), and Glucosamine 6 phosphate isomerase 2 (GNPDA2) between PD and AD. An inverse correlation between GNPDA2 and α-synuclein protein levels was also reflected in PD cerebrospinal fluid (CSF). Interestingly, PD patients exhibited significantly lower serum GNPDA2 levels than controls (n=82/group). Our study provides important avenues for understanding the OB proteostasis imbalance in PD, deciphering mechanistic clues to the equivalent smell deficits observed in AD and PD pathologies.