Impaired unfolded protein response, BDNF and synuclein markers in postmortem dorsolateral prefrontal cortex and caudate nucleus of patients with depression and Parkinson's disease
Unai Sarriés-Serrano, Lluís Miquel-Rio, Noemí Santana, Verónica Paz, María Sancho‐Alonso, Luís F. Callado, J. Javier Meana, Analı́a Bortolozzi
Abstract
Major depressive disorder (MDD) is characterized by significant impairment in social, emotional, and cognitive functioning. Its precise pathophysiology remains poorly understood. Alterations in protein homeostasis and some misfolded proteins have been identified within the brains of patients diagnosed with neuropsychiatric disorders. In contrast to neurodegenerative processes such as Parkinson's disease (PD), where the accumulation of aggregated α-synuclein (α-Syn) protein is a primary cause of significant neuronal loss, altered proteostasis in MDD may result in loss-of-function effects by modifying synaptic neuroplasticity. Moreover, aberrant activation of endoplasmic reticulum (ER) pathways may intensify the pathological alterations due to altered proteostasis. In this study, dorsolateral prefrontal cortex (dlPFC) and caudate nucleus from MDD patients and non-psychiatric controls were used. Postmortem samples of same brain areas from PD patients (Braak 2–3 and 5–6) and controls were also included. Protein levels of ER and unfolded protein response (UPR), synucleins (α-, β- and γ-Syn), and brain-derived neurotrophic factor (BDNF) were measured by Western-Blot. Phospho-eIF2α/eIF2α ratio was increased in the dlPFC and caudate nucleus of MDD and PD patients compared to their respective controls. Brain area-dependent changes in BiP and GRP94 levels were also found. We further detected accumulation of immature BDNF precursors and opposite changes in α- and β-Syn levels in the dlPFC of MDD and PD patients compared to controls. Our findings suggest that alterations in proteostasis contribute to the pathophysiology of MDD, as previously described in PD. A deeper understanding of the pathways involved will identify other candidate proteins and new targets with therapeutic potential. • Uncovering common proteostasis pathways that contribute to the pathophysiology of depression and PD, which often co-exist. • Impairment of PERK-eIF2α signaling mainly in dlPFC in patients with depression and PD. • Opposite changes in α-Syn and β-Syn proteins in dlPFC, with a decrease in depression and an increase in PD. • Higher proBDNF/mBDNF ratio in dlPFC and caudate nucleus associated with both pathologies.