Alpha-synuclein (α-syn) is the main protein component of Lewy bodies (LBs), that 
together with nigrostriatal dopamine neuron loss constitute typical pathological 
hallmarks of Parkinson's disease (PD). Glutamate N-methyl-d-aspartate receptor 
(NMDAR) abnormalities, peculiarly involving NR2B-containing NMDAR, have been 
observed in the brain of PD patients and in several experimental models of the 
disease. Recent findings, indicating that α-syn can modulate NMDAR trafficking 
and function, suggest that this protein may be a pivotal regulator of NMDAR 
activity. Prompted by these evidences, we used fluorescence immunocytochemistry, 
western blotting and ratiometric Ca(2+) measurements to investigate whether wild 
type (wt) or C-terminally truncated α-syn can specifically modulate 
NR2B-containing NMDAR levels, subcellular trafficking and function. In addition, 
we evaluated whether the exposure of primary cortical neurons to increasing 
concentrations of rotenone could differentially regulate NR2B levels and cell 
viability in the presence or in the absence of α-syn. Our results indicate that 
both wt and C-terminally truncated α-syn negatively modulate NR2B-containing 
NMDAR levels, membrane translocation and function. Moreover, we found that 
absence of α-syn abolishes the rotenone-dependent decrease of NR2B levels and 
reduces neuronal vulnerability in primary cortical neurons. These findings 
suggest that α-syn can modulate neuronal resilience by regulating 
NR2B-containing NMDAR, whose specific alterations could connect α-syn pathology 
to neuronal degeneration in PD.