Figure 7.

Proposed model for NM synthesis in SN DA neurons. 1) l-DOPA is taken up by a plasma membrane amino acid transporter. 2) l-DOPA is synthesized endogenously by tyrosine hydroxylase (TH). 3) DA is produced by aromatic acid decarboxylase (AADC). 4) Additional cytosolic DA is by the DA uptake transporter. 5) Synaptic vesicles (SV) and endosomes (not shown) accumulate cytosolic DA via VMAT2. 6) Cytosolic DA is metabolized in mitochondria (Mito) via monoamine oxidase. 7) Excess cytosolic DA and DOPA is oxidized via iron catalysis to quinones and semiquinones in the cytosol. 8) Quinones react with cysteine, proteins, and lipids. 9) DA-derived quinones and DA adducts in the cytosol and organelles are phagocytosed in bilamellar autophagic vacuoles/lysosomes where they are permanently stored as NM. 10) Damage from quinone-derived adducts that are not accumulated in NM granules promote neurodegeneration.