Submicron Crystals of the Parkinson’s Disease Substantia nigra: Calcium Oxalate, Titanium Dioxide and Iron Oxide

Abstract

Parkinson's disease (PD) results of the death of dopaminergic neurons of the substantia nigra. When activated, the NLRP3 inflammasome of phagocytes releases inflammatory agents, their release resulting in the death of proximal cells. The hallmark protein of PD, aggregated α-synuclein, is phagocytized and activates the NLRP3 inflammasome. Because crystalline particles are known to activate the NLRP3 inflammasome, to enhance α-synuclein expression and aggregation in dopaminergic neurons and because their facets may mis-template adsorbed α-synuclein, we probe here, by transmission electron microscopy (TEM), four human PD substantia nigra specimens for their crystalline particles. Samples weighing 5 mg of PD stages 1, 2, 4 and 5 were processed by proteolysis and centrifugation. TEM-grids were dipped in the centrifugate diluted to 1 mL and the dried films were searched for crystalline particles. Two types of crystalline particles, known to activate the NLRP3 inflammasome were found. Endogenous calcium oxalate, a downstream product of ascorbate and dopamine oxidation-produced hydrogen peroxide; and TiO2, the with pigment of foods and medications. The number-density of the NLRP-inflammasome activating crystalline particles found approached the reported about-equal number-densities of microglia and neuronal cells in the brain.The observations of COD and protein-coated TiO2 support two putative feedback loops, both leading to dopaminergic neuron death. In one, polymeric oxidized-dopamine catalyst accelerates H2O2-generation, the H2O2 indirectly oxidizing ascorbate in an ascorbate-fueled, oxalate-generating, loop the excess oxalate precipitating the subsequently inflammasome-activating COD crystals; In the second, protein-adsorbing facets of TiO2 mis-template the aggregation of α-synuclein to produce inflammasome-activating misfolded α-synuclein.