"There are two hypotheses of cell death of DA neurons based on two histopathological hallmarks in PD, i.e., the α-synuclein hypothesis (an α-synucleinopathy) and the NM hypothesis (Figure 1).
The α-synuclein hypothesis on the possible molecular mechanism of neuronal death of DA neurons in PD may be summarized as follows: Mitochondrial oxidant stress by various exogeneous or endogenous factors may produce mitochondrial dysfunction, especially complex I deficiencies [ 82 – 87], oxidation of DA in cytoplasm [64 ,88 ,89 ], and formation of oxidized DA accumulation, especially toxic 3,4-dihydroxyphenylacetaldehyde (DOPAL), formation of toxic ROS, accumulation of cytotoxic fibrillar aggregates of α-synuclein oligomers, mitophagy/autophagy dysfunction, and neuroinflammation [90– 97 ]. DOPAL is thought to accumulate in PD due to the low aldehyde dehydrogenase activity that oxidizes DOPAL to DOPAC in the SN in PD [98] and DOPAL generates potential reactive intermediates as causative agents for its neurotoxicity [99,100]"
"In the NM hypothesis, NM alone is related to DA neuron death. This review focuses on two independent ways of PD pathology, α-synuclein and NM. While both pathways may indeed lead to dopaminergic cell death, a decisive link between them is proposed “iron”, as pointed out recently by Riederer et al. [ 106 , 112 ,113 ]. The pathophysiology of NM decrease in the SN of DA neurons as a hallmark of PD remains unknown, especially in its relation to DA neuron death. In parallel with the elucidation of the chemistry and biosynthesis of NM in the DA neurons in the SN in PD, the physiological and pathological roles on NM have been studied since 2000s. NM in the SN increases gradually during aging in healthy subjects [21 ]. In contrast, NM decreases in PD. In PD, DA neurons containing NM in the human SN might preferentially degenerate, in parallel with the marked reduction in NM in the SN [ 114 ]. This fact, although controversial, suggests that NM is related to neurodegeneration and DA neuron death."
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Bolt_Upright
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I have always found this an interesting field and very fascinating to be honest, and had I been at school again instead of 40 years ago this is another one of those fields I would have loved to specialize in, except that I would have had to get my PhD in biochemistry which to be honest is a lot harder field than psychology, at least to me. A lot of diseases are based on the genetic and epigenetic mechanisms involved in apoptosis and other forms of programmed cell death, and some of which include immunological mechanisms. The chemistry is immensely complex, except sometimes it can be simple, is in the case of certain genes that carry both the signal to carry on and the signal to die in one or two chemical differentials, and again that simplicity is just fascinating. It covers all the cancers but also what's to immunological inputs to many neurodegenerative diseases. One can spend a lifetime learning about it much less making a specialty adding to the scientific knowledge base (a typical condition to get your Ph.D) and then as a career. But many others are cable of the critical reasoning, badly needed among those who actually consume research... It is as important to consume research competently as it is to create it. Best of luck and encouragement to everyone who would like to try and take a shot at it from where you stand, because there are many good minds around once they learn about reasoning, and about examining one's own self as a potential source perhaps even the likely source of bias and error no less than any other variable in scientific inquiry. You can spend a lot of hours doing less valuable pursuits. Remember to be humble and eschew simplistic thinking, and it's to everyone's benefit once you're accepted challenge and require yourself to meet a few standards. We're all capable of it if we only raise the bar upon ourselves a little bit more. Besides, it beats the hell out of playing the "Aint It Awful" and "Poor Me" game, far more satisfying no matter what your disability and how far along it is. Trust me on that, I have plenty of illnesses like every one of us. You just have to keep your existential philosophical mindset intact...nobody is entitled to better than they have, horrible as it truly is... Nobody is entitled to anything, including tomorrow. Try to make the best of it and hold your dignity. Yes we all suffer, and some horribly more than others. Acknowledged. That's the Truth. And a real existentialist will say, legitimately, "So what?"
Meanwhile if you want to talk about the mechanisms of cell death, cancer researcher SharonCrayn might definitely be somebody to ask questions.. but you have to ask her specifically, and ask nicely. She's on this forum.
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