Fig. 5

Crosstalk between dysregulation of metal ions and pathological proteins in neurodegenerative diseases. Excessive iron affects α-synuclein aggregation, while misfolded α-synuclein accelerates iron deposition. There are two copper-binding sites in the N-terminus of α-synuclein that increase its aggregation. Silencing CTR1 can decrease the phosphorylation and aggregation of α-synuclein. PARK9 deficiency induces increased zinc levels and α-synuclein aggregation. Manganese can indirectly stimulate the expression of α-synuclein through activating the ERK1/2 MAPK pathway. On the other hand, α-synuclein aggregation could enhance manganese-induced neurotoxicity through the NF-κB pathway. The binding of IRP to iron inhibits the IRE, which increases the expression of APP. APP can be cleaved by β- and γ-secretase in early endosomes to form Aβ in the amyloidogenic pathway. On one hand, excessive metal ions induce increased levels of Aβ monomers; on the other hand, metal ions can bind to Aβ and promote its aggregation. Iron, copper, and zinc enhance tau phosphorylation by activating CDK5, GSK-3β, or MAPKs and inactivating PP-2A activity to accelerate the formation of NFTs. Manganese exposure promotes the development of ALS. Additionally, partial deficiency of SOD2 significantly exacerbates motor deficits. Iron dysregulation induced by SOD1^G93A is mediated by impairment of the Akt/FOXO3a signaling pathway. Meanwhile, increased levels of copper, zinc, and metallothioneins-I/II/III are observed in SOD1^G93A mice. Copper has the ability to bind with the N-terminus of HTT proteins, thereby promoting their aggregation. Mutant HTT can lead to a deficiency in neuronal manganese, which affects arginase activity. Additionally, mutant HTT inhibits the binding of Sp1 to the promoter of the ZnT3 gene, resulting in decreased levels of synaptic vesicular zinc in the hippocampus, cortex, and striatum. This figure was created with BioRender.com/q53d457