Age- and brain region-dependent α-synuclein oligomerization is attributed to alterations in intrinsic enzymes regulating α-synuclein phosphorylation in aging monkey brains

Abstract

We previously reported that the levels of α-syn oligomers, which play pivotal pathogenic roles in age-related Parkinson's disease (PD) and dementia with Lewy bodies, increase heterogeneously in the aging brain. Here, we show that exogenous α-syn incubated with brain extracts from older cynomolgus monkeys and in Lewy body pathology (LBP)-susceptible brain regions (striatum and hippocampus) forms higher amounts of phosphorylated and oligomeric α-syn than that in extracts from younger monkeys and LBP-insusceptible brain regions (cerebellum and occipital cortex). The increased α-syn phosphorylation and oligomerization in the brain extracts from older monkeys and in LBP-susceptible brain regions were associated with higher levels of polo-like kinase 2 (PLK2), an enzyme promoting α-syn phosphorylation, and lower activity of protein phosphatase 2A (PP2A), an enzyme inhibiting α-syn phosphorylation, in these brain extracts. Further, the extent of the age- and brain-dependent increase in α-syn phosphorylation and oligomerization was reduced by inhibition of PLK2 and activation of PP2A. Inversely, phosphorylated α-syn oligomers reduced the activity of PP2A and showed potent cytotoxicity. In addition, the activity of GCase and the levels of ceramide, a product of GCase shown to activate PP2A, were lower in brain extracts from older monkeys and in LBP-susceptible brain regions. Our results suggest a role for altered intrinsic metabolic enzymes in age- and brain region-dependent α-syn oligomerization in aging brains.

Phosphorylated Alpha-Synuclein in Red Blood Cells as a Potential Diagnostic Biomarker for Multiple System Atrophy: A Pilot Study

“…e ELISA assay used for measuring pS-α-syn-RBC was established previously [25] and has been applied to detect pS-α-syn in aging monkey brains [24][25][26] and pS-α-syn formed in PD plasma [27]. e detection antibody was 3D5 mouse monoclonal anti-α-syn, which recognizes a sequence of 115-121 amino acids specific to human α-syn [23] and has been demonstrated previously for its specificity in detecting α-syn in human RBCs [16].…”

Targeting AMPK Signaling as a Neuroprotective Strategy in Parkinson’s Disease

“…However, in PD αSyn becomes increasingly phosphorylated at serine 129 (pS129), and over 90% of αSyn within Lewy bodies is phosphorylated [190,191]. Unphosphorylated αSyn activates the phosphatase PP2A, which promotes the dephosphorylation of both αSyn and AMPK, whereas pS129-αSyn inhibits PP2A [192,193]. Furthermore, pS129-αSyn was found to sequester PIKE-L, an inhibitor of AMPK, leading to increased AMPK activity in mice and in SH-SY5Y cells overexpressing αSyn [189].…”

“…Furthermore, pS129-αSyn was found to sequester PIKE-L, an inhibitor of AMPK, leading to increased AMPK activity in mice and in SH-SY5Y cells overexpressing αSyn [189]. Thus, unphosphorylated αSyn may inhibit AMPK function through PP2A, but as αSyn becomes increasingly phosphorylated this inhibition declines and other AMPK regulating proteins become inhibited, leading to increased AMPK activity [193]. Yet increased AMPK in these conditions may not necessarily correspond with normal physiological AMPK activation.…”

“…There is some evidence that pS129 reduces αSyn toxicity and promotes its macroautophagic clearance [195]. However, other studies have observed that pS129 increases the toxicity of αSyn and promotes aggregation [171,193]. The pathological role of pS129 may change across the course of PD.…”

The PP2A/4/6 subfamily of phosphoprotein phosphatases regulates DAF-16 during aging and confers resistance to environmental stress in postreproductive adultC. elegans

“…The level and activity of PP2A detected in postmortem brains of Alzheimer’s patients are, in fact, reduced compared to healthy controls (23). Similarly, low PP2A activity in monkey brains is associated with elevated levels of phosphorylated alpha-synuclein, a hallmark of Parkinson’s disease (24, 25). Outside of the context of acute disease, PP2A activity in the liver of SAMP8 mice is reduced and is correlated with increased levels of inactive, phosphorylated FoxO1 which may be responsible for the animals’ shortened lifespan (26).…”