The Protective Effect of Calbindin-D28K on a-Synuclein Aggregation in α- Synucleinopathies

Abstract

Neurodegeneration in Dementia with Lewy Bodies (DLB) and Parkinson's disease (PD) is associated with the formation of neuronal inclusion bodies composed mainly of aggregated α-synuclein (α-syn) protein. Aggregation may be associated with disturbed Ca2+ homeostasis and oxidative stress. Post-mortem studies have shown relative sparing of neurons in PD that are positive for the Ca2+ buffering protein, Calbindin-D28k (CB). CB has been shown to be induced by the hormonal form of vitamin D, Calcitriol, and could be induced by other vitamin D analogue such as Calcipotriol (Cp). Furthermore, recent cell culture and in vitro studies have shown that α-syn aggregation can be induced by potassium depolarization, hence we hypothesized that Cp may suppress their formation. We investigated the interplay between α-syn aggregation, expression of the calbindin-D28k (CB) Ca2+-buffering protein and oxidative stress in neurons by comparing DLB and "healthy" human brain tissue and examining a unilateral oxidative stress lesion model of α-syn disease (rotenone mouse), using the combination of immunofluorescence double labelling and Western blot (WB) analysis. DLB cases showed a greater proportion of CB-positive (CB+) neurons in affected brain regions compared to normal cases. Lewy bodies were present predominantly in CB-negative (CB-) neurons and were virtually undetected in CB+ neurons.