α-Synuclein Heterocomplexes with β-Amyloid Are Increased in Red Blood Cells of Parkinson’s Disease Patients and Correlate with Disease Severity

Abstract

Neurodegenerative disorders (NDs) are characterized by abnormal accumulation/misfolding of specific proteins, primarily α-synuclein (α-syn), β-amyloid1–42 (Aβ1–42) and tau, in both brain and peripheral tissues. In addition to oligomers, the role of the interactions of α-syn with Aβ or tau has gradually emerged. Nevertheless, despite intensive research, NDs have no accepted peripheral markers for biochemical diagnosis. In this respect, Red Blood Cells (RBCs) are emerging as a valid peripheral model for the study of aging-related pathologies. Herein, a small cohort (N = 28) of patients affected by Parkinson’s disease (PD) and age-matched controls were enrolled to detect the content of α-syn (total and oligomeric), Aβ1–42 and tau (total and phosphorylated) in RBCs. Moreover, the presence of α-syn association with tau and Aβ1–42 was explored by co-immunoprecipitation/western blotting in the same cells, and quantitatively confirmed by immunoenzymatic assays. For the first time, PD patients were demonstrated to exhibit α-syn heterocomplexes with Aβ1–42 and tau in peripheral tissues; interestingly, α-syn-Aβ1–42 concentrations were increased in PD subjects with respect to healthy controls (HC), and directly correlated with disease severity and motor deficits. Moreover, total-α-syn levels were decreased in PD subjects and inversely related to their motor deficits. Finally, an increase of oligomeric-α-syn and phosphorylated-tau was observed in RBCs of the enrolled patients. The combination of three parameters (total-α-syn, phosphorylated-tau and α-syn-Aβ1–42 concentrations) provided the best fitting predictive index for discriminating PD patients from controls. Nevertheless further investigations should be required, overall, these data suggest α-syn hetero-aggregates in RBCs as a putative tool for the diagnosis of PD.

GlialHMOX1expression promotes central and peripheral α‐synuclein dysregulation and pathogenicity in parkinsonian mice

“…In both the WT and GFAP.HMOX1 mice, we observed a progressive decline in serum miR‐153 and miR‐223 concentrations between 11 and 19 months of age. These findings correlate with age‐related increases in nigrostriatal and peripheral α‐synuclein expression reported in humans and monkeys (Barbour et al, ; Chu & Kordower, ; Daniele et al, ; Daniele et al, ; Matsumoto et al, ). miR‐153 levels were significantly lower in GFAP.HMOX1 serum than WT serum at each time point surveyed, suggesting that miR‐153, more so than miR‐223, may be responsible for upregulation of peripheral α‐synuclein expression under pathological (parkinsonian) conditions.…”

A Comparative Study of the Diagnostic Potential of Plasma and Erythrocytic α-Synuclein in Parkinson’s Disease

“…However, the amount of α-Syn in plasma inversely correlated well with the age of PD patients, and an inverse correlation between the level of erythrocytic α-Syn and age was also found, albeit without statistical significance. Our results support previous research and demonstrates that the level of α-Syn could be overcome by the effect of age [25].…”

Systemic Activation of Nrf2 Pathway in Parkinson's Disease

“…29,30 Moreover, they can also activate the Nrf2 pathway synergistically. 12,[31][32][33] We found that α-syn oligomers, whose increase in cerebrospinal fluid or other blood fractions of PD patients is now considered a marker of synucleinopathy, 17,[34][35][36][37][38] were increased even in the peripheral leukocytes of PD patients. Likewise, we also observed a significant decrease of the mitochondrial CI activity, particularly when normalized to the levels of CS (a marker of mitochondrial mass), which was consistent with a specific enzyme's defect.…”

“…In this pilot cross‐sectional study, we attempted to outline the peripheral profile of the Nrf2 pathway in the blood of PD patients with the aim to establish its potential clinical value. Peripheral blood is now considered a significant and easily accessible source of biomarkers for neurodegenerative diseases, as it might mirror pathological changes occurring both at the central nervous system and cerebrospinal fluid levels . In addition, to link the Nrf2 pathway activity to relevant features of PD, we analyzed its correlation with both the main clinical features of the disease and the blood leukocytes levels of α‐synuclein (α‐syn) oligomers.…”