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Degraded protein

Fig. 1. For legend see opposite page.

Schematic diagram of major gene and neurochemical alterations in human SNpc of PD. Gene expression analysis of SNpc of PD has confirmed and extended the previously established complexities by which dopaminergic neurons degenerate. These findings do not allow a conclusion to be reached regarding the primary biochemical event(s) that induces the "domino" death cascade. OS, resulting from excessive generation of nitric oxide/peroxynitrite (NO/ONOO-), O2, or hydroxyl radicals, can lead to dysregulation of iron metabolism, induction of a-synuclein aggregation, and mitochondrial dysfunction. Free (labile) iron itself can cause OS, aggregation of a-synuclein, and degradation of iron regulatory protein 2 (IRP2) via activation of egl nine homologue 1 (C. elegans) (EGLN1), which is a key iron and OS sensor. This in turn results in proteasomal degradation of hypoxia-inducible factor (HIF) and IRP2, with subsequent decreases in cell survival/proliferation, glucose, and iron metabolism genes. Parallel, an increase in gene expression of HIF-1 responsive RTP801 (RTP801) was found in PD SN. Increases in the expression of cell adhesion molecules and components of the extracellular matrix in response to OS/free radicals can result in cell assembly disruption. Aldehyde derivatives of dopamine metabolism are highly neurotoxic, and aldehyde dehydrogenase (ALDH) is the key enzyme for their metabolism to inert acidic metabolites (homovanillic acid and dihy-droxyphenylacetic acid). The reduction in gene expression of ALDH1A1, ARPP-21, and VMAT2, which are located within dopamine-containing neurons of SNpc, may contribute to a failure in DA transmission and metabolism. Significant evidence has been provided for involvement of protein misfolding in dopamine neuronal death. SKP1A is part of the SCF (SKP, Cullin, F-box protein) ubiquitin ligase component (E3) that regulates normal degradation of a wide arrays of proteins, which may include a-synuclein, parkin, IRP2, HIF, etc. Its decline can cause evasion of proteins subjected to SCF/26S proteasome complex degradation. This protein processing is exacerbated if some of the 26S proteasome subunits are downregulated (PSM), as observed in several studies, since they are an integral part of the regulatory and catalytic activity of the proteasome. The ubiquitin activating enzyme-1 (UBE1) seems also to alter its expression which may influence the SCF process. The decreased expression of the chaperone HSC-70 may affect the correct folding of several proteins that are specifically ubiquitinated by the co-chaperone carboxyl-terminus of HSC-70 interacting protein (CHIP), as well as parkin-CHIP-mediated ubiquitination, and may increase aggregation of a-synuclein and iron-induced OS. Another protein involved in this processes was found to have a decrease expression in PD, the UCHL1 or so-called PARK5 (ubiquitin carboxyl-terminal esterase L1). In addition, the mitochondrial disfunction that is also known in MPTP model for PD was supported by the decreased expression of several NADH dehydrogenase proteins (NDU). Red boxes are for up-regulated genes and blue boxes are for down-regulated genes. Sharp arrows indicate positive inputs, whereas blunt arrows are for inhibitory inputs (Modified from Reference (62)).

Fig. 2. Schematic diagram of vesicular transport in the cell. Through the new methodology the involvement of vesicular transport was revealed, which seems to be much more complex than only the involvement of VMAT2. Red boxes are for-up-regulated genes and blue boxes are for down-regulated genes. Abbreviations: Stxbp1, syntaxin-binding protein; Stx6, syntaxin-6; SYT1, synaptotagmin I; SV2C, synaptic vesicle protein 2C; SNX10, sorting nexin 10; SNAP25, synaptosomal-associated protein, 25 kDa; RAB2, member RAS oncogene family; VAMP1, vesicle-associated membrane protein-1; VMAT2, solute carrier family 18 (vesicular monoamine transporter); Sec22, Sec22 vesicle trafficking protein (Modified from KEGG: <http://firez.scl.genome.ad.jp/kegg/>/).

Fig. 2. Schematic diagram of vesicular transport in the cell. Through the new methodology the involvement of vesicular transport was revealed, which seems to be much more complex than only the involvement of VMAT2. Red boxes are for-up-regulated genes and blue boxes are for down-regulated genes. Abbreviations: Stxbp1, syntaxin-binding protein; Stx6, syntaxin-6; SYT1, synaptotagmin I; SV2C, synaptic vesicle protein 2C; SNX10, sorting nexin 10; SNAP25, synaptosomal-associated protein, 25 kDa; RAB2, member RAS oncogene family; VAMP1, vesicle-associated membrane protein-1; VMAT2, solute carrier family 18 (vesicular monoamine transporter); Sec22, Sec22 vesicle trafficking protein (Modified from KEGG: <http://firez.scl.genome.ad.jp/kegg/>/).

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