Rodent imaging centers overlap, KBigD studies (KH Park 2020 18F-PR-PE2I MPTP-mouse / Js 2019 11C-PE2I 6-OHDA-rat / AAV SNCA-rat), Charles Rivers studies, SWEDD section (Marek 2018 #1283 PD PROTOpos), Neuromelanin pigment definition / Expression / DISTRIBUTION / Synthesis pathway diagram (DA → DA-quinones → DA-protein adducts → Pheomelanin → Eumelanin / Neuromelanin organelle)
SWEDD
PD PROTOpos (Marek, 2018 #1283)
- A DaT scan could be considered at baseline in order to exclude individuals who have scans without evidence of dopaminergic deficit (SWEDD), which may comprise around 10-15% of subjects with early stage PD (e.g. PD subjects within 9 months of diagnosis).
- Longitudinal studies indicate that SWEDD subjects have minimal evidence of clinical or imaging PD progression over time (Marek et al. 2014).
- Eliminating SWEDD subjects could reduce clinical trial sample size by about 20% (Marek et al. 2014).
Neuromelanin pigment
definition
- Neuromelanin (NM) (or NM-pigment, melanin), is a dark-colored pigment found in the brain which is structurally related to melanin.
- It is a polymer of 5,6-dihydroxyindole monomers.
Expression
- Neuromelanin is expressed in large quantities in catecholaminergic cells of the substantia nigra pars compacta and locus coeruleus, giving dark color to the structures.
- Neuromelanin concentration increases with age, suggesting a role in neuroprotection (neuromelanin can chelate metals and xenobiotics) from ROS or senescence.
- Studies have also shown that neuromelanin containing dopaminergic neurons of the SNc are more subjected to degeneration in patients with PD than dopaminergic neurons that do not contain melanin. (i): there seems to be two types of DA neurons: melanin-containing and melanin-absent).
- Pathway:
- directly biosynthesized from L-DOPA (precursor to dopamine), by aromatic acid decarboxylase (AADC), is, but the below pathway seems to predominate over this one.
- Alternatively, if synaptic vesicle and endosome accumulate cytosolic dopamine (via VMAT2), and transport it to mitochondria where it is metabolized by monoamine oxidase (MAO).
- Excess dopamine and DOPA molecules are oxidized by iron catalysts into dopaquinones and semiquinones which are then phagocytosed and are stored as neuromelanin.
DISTRIBUTION of neuromelanin
The concentration of NM pigment in normal SN increases by about 50% between the ages of 40 and 60.
Detection of neuromelanin pigment (granule)
- NM pigment accumulates inside specific autophagic organelles, which contain NM-iron complexes, along with lipids and various proteins (3, 4).
- NM-containing organelles accumulate gradually over the lifespan in the soma of dopamine catecholaminergic neurons of substantia nigra (SN)
- NM-containing organelles are only cleared from tissue following cell death (The NM-iron complex can be found in an extracellular compartment after neuronal death.5,6,7,8(7,18,19))
COMPONENTS of neuromelanin pigment
Within the autophagic organelles, NM pigment consists of granular aggregates of 200-400 nm composed of smaller spherical substructures of ~30 nm diameter (3,30,31 due form (cell)) which can form spherical electron-dense aggregates. In NM, the melanin components are covalently bound to peptides that have cross β-sheet structure and aliphatic chains derived from dolichol and dolichoic acid (dolicho-poly compound). The dolichols and dolichoic acids 3,2 are the major constituents (3,4,33-35 of unggested) (lipids bodies’ melanin aggregates / NM-containing organelle).
The protein components are aSyn, antigen presenting proteins, MHC I.
Synthesis process of neuromelanin granule (pigment)
| step | action | This step is enhanced by iron and other redox metals |
|---|---|---|
| 여기에 protein (aggregated & β structured)이 들어와 | Neuromelanin is produced by the autoxidation of dopamine or NE in cytosol | |
| 여기에 iron이 들어와 | ||
| Autophagy 기전 |