main factors contributing to the complex ... - Cure Parkinson's
main factors contributing to the complex basis of Parkinson
Dekker's observations on rural-dwelling Maasai and Hadza and the absence of PD in their populations is a BIG clue to the over-arching importance of sunlight and vitamin D3 in the etiology of PD. These two populations are the very same as regarded by most D3 researchers as having a physiological level of D3. eg section 2.3 here: mdpi.com/2072-6643/12/7/2097
Hi Farooqji,
Thanks for sharing. If you don't mind, I have taken the liberty of summarizing and extracting the information in the article with the help of Artifical Intelligence (AI).
Response 1:
Here is a review and summary of the article:
Title: Different pieces of the same puzzle: a multifaceted perspective on the complex biological basis of Parkinson’s disease
Journal: npj Parkinson's Disease
Key Points:
- The biological basis of Parkinson's disease (PD) remains unclear despite over 200 years of research. There are varying theories regarding its pathobiology.
- 13 experts from around the world provide their perspectives on what triggers PD development and the underlying biological processes.
- Views range from toxin exposure as a trigger, to mutations in genes like LRRK2 being a root cause, to toxic alpha-synuclein accumulation being most important.
- Genetic factors like mutations in PRKN, PINK1, SNCA and LRRK2 increase risk, but are not fully penetrant on their own.
- Mitochondrial dysfunction and alpha-synuclein accumulation interact and have a central role in pathogenesis.
- Exposure to toxins like pesticides, especially paraquat, are linked to PD and may trigger disease in susceptible individuals.
- Alpha-synuclein spreads in a prion-like fashion between brain regions and the gut, potentially driving progression.
- PD may be better defined as multiple related diseases rather than a single entity, with complex interactions of genetic and environmental factors.
In summary, the article brings together expert opinions that highlight the complexity of PD's underlying biology and etiology. While progress has been made identifying genetic and environmental risk factors, no single pathway fully explains PD. The disease likely results from multiple triggers exceeding a threshold of neuronal stress and damage.
Response 2:
Here are some additional details from the article:
- Mutations in LRRK2 are highlighted as a major genetic risk factor, with variants conferring the highest individual risk. Increased LRRK2 kinase activity is implicated as a causal factor in both familial and sporadic PD.
- Toxin exposure, particularly to pesticides like paraquat and rotenone, is linked to increased PD risk and earlier onset. Areas with high agricultural toxin usage, like certain regions in South America, may have elevated PD rates.
- Alpha-synuclein aggregates and spreads between neurons in a prion-like manner. Propagation may occur from the gut to the brain or within the CNS. Imaging tools can detect spread and associated neurodegeneration.
- Mitochondrial dysfunction is proposed to both directly cause alpha-synuclein accumulation and indirectly via impaired protein clearance pathways. A vicious cycle may ensue.
- Studies in African populations suggest genetic factors may play a smaller role, while agricultural exposures could be more important triggers. Comparing groups with low exposure may provide insights.
- No single model fully explains PD onset - it may arise via gene-environment, gene-gene, or environment-environment interactions exceeding neuronal tolerance thresholds.
- Future research priorities include studying toxin exposures and genetic risks in underrepresented populations, developing exposure biomarkers, and evaluating disease mechanism convergence across models.
In summary, the article integrates diverse expert views to outline the multifaceted and complex nature of PD biology, with interactions between multiple genetic and environmental factors contributing to disease.
Response 3
Here are some additional details from specific perspectives presented in the article:
- Matthew Farrer emphasizes evidence that increased LRRK2 kinase activity drives both familial and sporadic PD, making it a major causal factor. Population-specific LRRK2 variants imply an environmental component to penetrance.
- Marieke Dekker notes studies showing a possible younger onset and higher prevalence of PD in Sub-Saharan Africa. Known genetic factors may play a smaller role, while chronic agricultural toxin exposures could be an understudied trigger.
- Nobutaka Hattori discusses how mitochondrial dysfunction from genes like CHCHD2 can drive alpha-synuclein accumulation, forming a vicious cycle. Abnormal alpha-synuclein from the gut may propagate via nerves and immune mechanisms.
- Irena Rektorová's work uses diffusion MRI and functional connectivity to track alpha-synuclein spreading between brain regions. Pathology appears to follow networked brain regions early in disease.
- Artur Schuh emphasizes evidence linking agricultural toxins like paraquat to increased PD risk and pathogenesis. Studying exposed populations could provide insights given loose toxin regulations in some regions.
- Mohamed Salama proposes a "threshold model" where diverse triggers accumulate stress until exceeding neuronal tolerance limits. This framework better incorporates disease heterogeneity than linear models.
- George Mellick advocates considering PD as a syndrome with many primary conditions, given rare Mendelian forms involve distinct processes. Unique trigger combinations lead to idiosyncratic disease trajectories.
Thanks for doing this. Appreciate it. Could you break down exactly how you did it using AI, please? No worries if that' too big an ask.
Sure Dabaa. I will prepare a write up f the forum today. I will include a cheatsheet/primer.
listen to the podcasts I posted today by Dr Chestnut.
His theory is every chronic disease is a disease of lifestyle (apart from a few true genetic diseases). He says genes don’t change quickly over time ie in a a couple of generations, so if the prevalence of disease is increasing that has to be lifestyle:
Food, exercise, exposure to toxic substances (chemical and biological), insufficiencies of nutrients and various light wavelengths and relationships/thoughts/mental stressors.
These can cause genes to switch on or off causing disease. To regain health the body’s environment must be improved to replicate the biologically pristine environment of our ancestors in each of the above respects.
eg if fish in a lake start dying we don’t give them a drug, or a procedure or set up a hospital. We say their environment has become unhealthy and do everything to fix the environment. Humans are mammals but instead of treating them in the same way you would other animals we have medical models, drugs , procedures and most doctors don’t take lifestyle seriously. It should be the first line of defence when disease strikes.
It’s a very compelling argument. So I would say that diagram is not quite right if dr chestnut is correct. Incorrect lifestyle leads to all of the other issues, one or more of which leads to PD or one of many other chronic conditions depending which of your genes is the most susceptible to being switched on/off.
Most drug companies are trying to find ways to get rid of the protein clumping. If lifestyle factors are all resolved his theory is slowly the body will begin to reverse mitochondrial dysfunction and damage. If this happens early in any disease it may be completely reversed. (I would think that there may reach a point of no return where the progression cannot be completely reversed).
the number one reason why people get Parkinsons disease is….
Bad luck!
I know this because none of my friends and family members have it, and they all rolled the same dice as me.
I like your diagram, though. Just thought I’d add my $0.02
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