DNA repair tail (Homology-directed / Non-homologous / Microhomology-mediated / Direct reversal / Translesion synthesis), DNA damage in PD (Sariguchi 2021 #1782 γH3AX / DNA glycosylase upregulation / NTH-1 decline with age), MOA in PD (BER capacity / SSB intermediates), Dopamine system / Catecholamine pathway (L-DOPA → DA → DOPAC / 3-MT / HVA / MAO / COMT illustrations + 18F-DOPA tracer), Dopamine metabolites in PD opener (Beriheimer 1973 #1749 postmortem 39 PD; LeWitt 2011 #1782 DATATOP CSF)

DNA damage in PD

(Sariguchi 2021 #1782) The genomic stress marker γH3AX is seen in neuronal cells from human PD patients (Sepe et al., 2016)

(Sariguchi 2021 #1782) Up-regulation of several DNA glycosylases in the substantia nigra (Bostwick et al. 2017; Fukae et al. 2005; Nakaboppu et al. 2007)

(Sariguchi 2021 #1782) Commonly expression and activity of NTH-1, the primary BER DNA polymerase, decline with age (Mosak et al. 2017; Sykora et al. 2015)

(Sariguchi 2021 #1782) Whole-exome sequencing data revealed AGGGTGTAGA in patients with idiopathic PD/AD; AC genome-wide significant attribution of variants in BER genes was found NTH1 in PD (LP60.0). Through pathway/baseline-incurred analyses for race nonsynonymous, missense, splice site variants using the SKAT-O test, a significant attribution of variants in BER genes was found Wishart et al. (Wright-PD), this enrichment was independent confirmed by a NIBL-an EWAS data analysis revealed significant enrichment of a single variant (rs1099511538, GtyM/A NIM2) These can be detected idol/417 PD cases) and 0/645 controls (Table 5,5).

MOA in PD

If amount of DNA damage exceeds the capacity of BER, if DNA recovery and inefficiently incompletely repaired, active BER can generate toxic SSB intermediates, such as un-strand breaks ((Sariguchi 2021) Incomplete repair of endogenous DNA base damage by NTH-1-initiated BER in both mitochondrial and nuclear DNA generates genomic stress during aging.

Dopamine system

Catecholamine pathway

step		L-Dopa	Cell uptake	(By AADC) tyrosinase / DOPA decarboxylase / dihydroxyphenylacetic L-DOPA → Dopamine	DA is transported from cytosol into the synaptic vesicle by VMAT	Vesicle released Dopamine into the synaptic cleft (by depolarization)	Dopamine pumped back into the cell by DAT or — others — surrounding cells by entering extracellular space being phagocyted by catechol O-methyltransferase	DA bind D1, D2 receptors (postsynaptic)
tyrosine (eg systemic)	L-Dopa	L-Dopa enters BBB	but other surrounding cells by entering extracellular space being phagocyted by catechol O-methyltransferase
penetrate the cells carried by the L-type amino acid transporter 1 and 2 (LAT1 and LAT2). These transporters are enriched in the BBB permeability of the blood brain barrier (BBB) of F-DOPA Excess (cytosolic) DA and DOPA are oxidized by iron and DOPAC and oxidized by ferric / ferrous Fe2+/Fe3+ as DOPA-quinones, dopaminones and semiquinones, are stored as neuromelanin
(oxidation of L-dopa) → neuromelanin	DBH		norepinephrine			PNMT EPINEPHRINE
[18F]-DOPA: total extracellular radioactivity in 18F-DOPA-strain was seen to rise and peak at 30 min post-injection, and then decline after a two-hour lapse corresponding to the dopamine half-life. (Calabria, 2017 #2809) Dihydroxyphenyldlactic acid (DOPAC) is a metabolite of dopamine. Dopamine can be metabolized into one of three substances. One such substance is DOPAC. Another is 3-methoxytyramine (3-MT). Both of these substances are degraded to form homovanillic acid (HVA). Both degradations involve the enzymes monoamine oxidase (MAO) and catechol-O-methyltransferase (COMT), albeit in reverse order. MAO catalyzes dopamine to DOPAC and COMT catalyzes DOPAC to HVA, whereas COMT catalyzes dopamine to 3-MT and MAO catalyzes 3-MT to HVA. The third metabolic end-product of dopamine is norepinephrine (noradrenaline). DOPAC can be oxidized by hydrogen peroxide, leading to the formation of toxic metabolites which destroy dopamine storage vesicles in the substantia nigra. This may contribute to the development of levodopa treatment of Parkinson's disease. A MAO-B inhibitor such as selegiline or rasagiline can prevent this from happening (citation needed).

Chemical-structure diagram

• Dopamine (DA)
• 3-Methoxytyramine (3-MT)
• 3,4-Dihydroxyphenylacetic acid (DOPAC)
• Homovanillic acid (HVA)
• Catechol-O-methyltransferase (COMT)
• Monoamine oxidase (MAO)

degradation of dopamine

Dopamine metabolites in PD — correlation between dopamine (& metabolite) and clinical

	study	cases	narrative
postmortem brain	(Beriheimer, 1973 #1749)	Postmortem, 39 PD cases, no normal control. Disease duration 9.3 SD 0.9	TABLE 10 — CORRELATION BETWEEN THE SEVERITY OF AKINESIA, TREMOR AND RIGIDITY AND THE INCREASE IN DA AND HVA IN THE STRIATUM. Figures represent means in mg/g ± S.E.M. Number of cases are presented in parentheses.
CSF	(LeWitt, 2011 #1782)	DATATOP study, 217 unmedicated early PD (H&Y 1-2.5) subjects	Interval between 1st & 2nd CSF collection 0.05 < P < 0.10

Uncertain Spans

location	transcription	uncertainty
DNA damage / whole-exome sequencing data revealed AGGGTGTAGA	reads as written; OCR-rendered with possible artefacts in the variant token; preserved verbatim.