An attempt to dissect a peripheral marker based on cell pathology in Parkinson's disease

Abstract

Peripheral markers in Parkinson’s disease (PD) represent a hot issue to provide early diagnosis and assess disease progression. The gold standard marker of PD should feature the same reliability as the pathogenic alteration, which produces the disease itself. PD is foremost a movement disorder produced by a loss of nigrostriatal dopamine innervation, in which striatal dopamine terminals are always markedly reduced in PD patients to an extent, which never overlaps with controls. Similarly, a reliable marker of PD should possess such a non-overlapping feature when compared with controls. In the present study, we provide a novel pathological hallmark, the autophagosome, which in each PD patient was always suppressed compared with each control subject. Autophagosomes were counted as microtubule-associated proteins 1A/1B light chain 3B (LC3)-positive vacuoles at ultrastructural morphometry within peripheral (blood) blood mononuclear cells (PBMC). This also provides the gold standard to assess the autophagy status. Since autophagy may play a role in the pathogenesis of PD, autophagosomes may be a disease marker, while participating in the biology of the disease. Stoichiometric measurement of α-synuclein despite significantly increased in PD patients, overlapped between PD and control patients. Although the study need to be validated in large populations, the number of autophagy vacuoles is neither related with therapy (the amount was similarly suppressed in a few de novo patients), nor the age in PD or controls.

Insulin-like growth factor 2 and autophagy gene expression alteration arise as potential biomarkers in Parkinson’s disease

“…The reduction of these genes from initial pathway complexes suggests a decrease in the formation of the autophagosome vesicles that surround the substrate. Recently, an ultrastructural study in PBMCs obtained from PD patients demonstrated fewer autophagy vacuoles per cell, supporting our results 96 . In particular, we found that the reduction of BECLIN1 and ATG5 in PBMCs of PD patients was aligned with the significant reduction in transcriptional levels of Atg5 and a tendency in Beclin1 in murine macrophages treated with α-synuclein.…”

Alterations in Proteostasis System Components in Peripheral Blood Mononuclear Cells in Parkinson Disease: Focusing on the HSP70 and p62 Levels

“…LC3-I to LC3-II conversion is elevated in PBMCs [24], and LC3 gene expression as well as LC3-II protein levels are significantly increased in the leukocytes of PD patients, indicating autophagosome accumulation [6]. On the other hand, the number of autophagy vacuoles per cell in PBMC of PD patients is decreased compared with healthy subjects [57]. The modulation of intracellular signaling implicated in neuronal cell survival, growth, proliferation, and metabolism in PD indicates that p62-involved autophagy activity is regulated at posttranslational and transcriptional levels [58].…”

Molecular Modulators and Receptors of Selective Autophagy: Disease Implication and Identification Strategies

“…Transmission election microscopy (TEM) is a gold standard to assess the status of autophagy. Recently, it has been successfully applied to analyze peripheral autophagy markers associated with PD 96 . TEM is recommended to be used to evaluate the efficacy of the screened receptors and modulators and investigate their functional implications for autophagy.…”