Figure 3.

Mn²⁺-related molecular pathways associated with the development of two neurodegenerative diseases: the Kufor-Rakeb syndrome (A) and prion-related disorders (B). (A) Specific mutations within the human gene ATP13A2 have been shown to induce misfolding of the α-syn protein and its subsequent neurotoxic aggregation that leads to the formation of Lewy bodies in human neurons. In parallel, mutated ATP13A2 has been shown to directly disturb manganese homeostasis, thereby establishing a connection between genetics (α-syn and ATP13A2) and environmental (unbalanced manganese exposure) causes of neurodegeneration. (B) The human protein PrP interacts, in its functional isoform (PrP^C), with copper, and also with manganese. This interaction with manganese has been suggested to induce the conversion of PrP^C to its proteinase-resistant counterpart PrP^Sc. In this form, PrP forms neurotoxic aggregates, thereby leading to the prion-disease associated symptoms.