This is an interesting PD review from Japan concluding:

"Logical approaches against PD progression include (i) reducing intracellular DA accumulation, (ii) blocking cytosolic Ca2+ oscillations, and (iii) providing bioenergetic support to PD patients".

To reduce DA accumulation they present a hypothesis "We assume that the regular DA release may explain the lesser PD risk of smokers", IMO an interesting hypothesis and may be better than my CO hypothesis.

They also explain the the possible role of calcium blockers which have been protective in getting PD. ( "A mitochondrial inside-out iron-calcium signal reveals drug targets for Parkinson's disease" by Stanford scientist in 2023).

Bioenergetic support is the easiest to agree on as an ATH investor based on how 434 improves both aerobic and anaerobic ATP production and also reduces oxidative stress ( Kosman's posters during the 2 last years).

Review

Int J Mol Sci

. 2024 Feb 7;25(4):2009.

doi: 10.3390/ijms25042009.

Parkinson's Disease: Cells Succumbing to Lifelong Dopamine-Related Oxidative Stress and Other Bioenergetic Challenges

Hirohisa Watanabe ¹, Johannes M Dijkstra ², Toshiharu Nagatsu ³

Affiliations Expand

• PMID: 38396687

PMCID: PMC10888576 DOI: 10.3390/ijms25042009

Abstract

The core pathological event in Parkinson's disease (PD) is the specific dying of dopamine (DA) neurons of the substantia nigra pars compacta (SNc). The reasons why SNc DA neurons are especially vulnerable and why idiopathic PD has only been found in humans are still puzzling. The two main underlying factors of SNc DA neuron vulnerability appear related to high DA production, namely (i) the toxic effects of cytoplasmic DA metabolism and (ii) continuous cytosolic Ca²⁺ oscillations in the absence of the Ca²⁺-buffer protein calbindin. Both factors cause oxidative stress by producing highly reactive quinones and increasing intra-mitochondrial Ca²⁺ concentrations, respectively. High DA expression in human SNc DA neuron cell bodies is suggested by the abundant presence of the DA-derived pigment neuromelanin, which is not found in such abundance in other species and has been associated with toxicity at higher levels. The oxidative stress created by their DA production system, despite the fact that the SN does not use unusually high amounts of energy, explains why SNc DA neurons are sensitive to various genetic and environmental factors that create mitochondrial damage and thereby promote PD. Aging increases multiple risk factors for PD, and, to a large extent, PD is accelerated aging. To prevent PD neurodegeneration, possible approaches that are discussed here are (1) reducing cytoplasmic DA accumulation, (2) blocking cytoplasmic Ca²⁺ oscillations, and (3) providing bioenergetic support.