Endoplasmic reticulum stress‑regulated chaperones as a serum biomarker panel for Parkinson’s disease

Examination of post-mortem brain tissues has previously revealed a strong association between Parkinson’s disease (PD) pathophysiology and endoplasmic reticulum (ER) stress. Evidence in the literature regarding the circulation of ER stress-regulated factors released from neurons provides a rationale for investigating ER stress biomarkers in the blood to aid diagnosis of PD. The levels of ER stress-regulated proteins in serum collected from 29 PD patients and 24 non-PD controls were measured using enzyme-linked immunosorbent assays. A panel of four biomarkers, protein disulfde-isomerase A1, protein disulfde-isomerase A3, mesencephalic astrocyte-derived neurotrophic factor, and clusterin, together with age and gender had higher ability (area under the curve 0.64, sensitivity 66%, specifcity 57%) and net beneft to discriminate PD patients from the non-PD group compared with other analyzed models. Addition of oligomeric and total α-synuclein to the model did not improve the diagnostic power of the biomarker panel. We provide evidence that ER stress-regulated proteins merit further investigation for their potential as diagnostic biomarkers of PD.</p

Inhibition of IRE1α RNase activity sensitizes patient-derived acute myeloid leukaemia cells to proteasome inhibitors

Despite improvements in prognostic stratification and optimization of therapeutic intervention in acute myeloid leukaemia (AML) patients, long-term survival is low. Clinical trials suggest proteasome inhibitors may be beneficial, but further interrogation of the molecular consequences of proteasome inhibition in AML is warranted to identify novel approaches that enhance their efficacy.1 In multiple myeloma (MM), resistance to proteasome inhibitors can occur upon activation of the unfolded protein response (UPR), a stress response pathway that can control cell fate.2 Inositol-requiring enzyme 1 alpha (IRE1α) is one of three stress sensors that mediates UPR signalling. IRE1α activity occurs via its RNase domain resulting in cleavage of a 26-nucleotide intron from X-Box Binding Protein 1 (XBP1) mRNA leading to formation of a transcription factor, XBP1s. XBP1s enhances cell survival by increasing transcription of genes associated with protein folding, endoplasmic reticulum-associated degradation (ERAD) and phospholipid synthesis. We demonstrate that an IRE1 RNase inhibitor (MKC8866), in combination with proteasome inhibitors, significantly decreases XBP1s levels and increases cell death in AML cell lines and patient-derived AML cells. In addition, this combination treatment can successfully target the CD34+CD38− population and reduce clonogenic ability.</p