It could be because alpha-synuclein regulates apoptosis via 3 other proteins: 14-3-3 which regulates cell viability, BAD which is pro-apoptosis and Bcl-2 which is anti-apoptosis. BAD will bind to Bcl-2 to inhibit it and allow apoptosis to begin. (apoptosis is controlled cell death, something your body does at least millions of times a day, but much less in the brain, in general it is safe and needed but unregulated apoptosis is not good).
If BAD is phosphorylated at a serine residue then 14-3-3 can bind to inhibit BAD, thus disinhibiting Bcl-2 to prevent apoptosis. Alpha-synuclein will interact with 14-3-3 to prevent it binding to BAD thus promoting apoptosis. However, this theory only explains PD if alpha-synuclein is being overexpressed. There is evidence that mutated alpha-synuclein is more likely to lead to PD due to incorrect folding. In addition, the aggregation of alpha-synuclein may interfere with ubiquitin which would lead to oxidative damage and therfore cell death, this may explain the presence of ubiquitin in Lewy bodies. Ubiquitin proteins have many roles so if this is the case then it could be many things. There is also the possibility of oxidative stress directly due to alpha-synuclein or oxidation that is independent of these mechanisms or the cause of these mechanisms. (e.g. oxidation could change the expression of alpha-synuclein).
Other potential cell death mechanisms:
Having already mentioned it lets talk about the theory of misfolding alpha-synuclein before going into the details it is important to note that this theory gives an explanation as to how cell death spreads to other neurons. In the above theory the overexpression would have to occur in all neurons but not start until around 55 (this highly rules out just a genetic answer) but the misfolding theory suggests that the misfolded alpha-synuclein leaves the neuron in vesicles and enters other neurons via endocytosis. It acts like a virus in a way, infecting more cells which is why the disease progresses rather than alpha-synuclein just being overexpressed in all cells which would cause the patient to go from fine to late stage PD. So this theory so far is more attractive. The theory states that misfolding causes the protein to be non-functional and hyper-aggregate which is what causes the formation of Lewy bodies, which then transfer to nearby neurons.
Protein misfolding is not as uncommon as it sounds with an estimated 1 in 3 translated, folded proteins are incorrect, whether it be in folding or damaging events after folding there are many opportunities for misfolding. For the most part molecular chaperones called heat-shock proteins can refold proteins or mark them for proteolysis. Usually ubiquitin tags targeted proteins forming a polymer that can be degraded by 26S proteasome. The misfolding of synuclein can form pore structures for other Lewy bodies to exit and 'infect' other cells. In PD synuclein aggregates heavily which can make the ubiquitin-proteasome pathway redundant because it is too aggregated to enter the proteasome pore to be degraded but cells have another system in place to prevent these aggregations causing damage. It is called macroautophagy and is a process of an autophagosome engulfing the aggregated protein and entering the lysosome via endocytosis where the whole thing is degraded. Autophagosomes are large enough to internalise whole organelles so can deal with large aggregated proteins but in PD the synuclein aggregates to a point that neither process works which causes either necrosis or apoptosis, leaving Lewy bodies behind. Once in the ECM they attract microglia and inflammation which causes more damage and increases symptoms.
ubiquitin-proteasome pathway: I have spoken a little about this just but I want to go into ubiquitin. Ubiquitin has 3 enzymes, E1 which is an activating enzyme, E2, a conjugating enzyme and a ligating enzyme- E3 also called parkin protein. This protein catalyses the oligomerisation of ubiquitin and proteins that need degrading. There are a few missence mutations that can appear in parkin that lead to misfolding of the enzyme preventing it from interacting correctly with ubiquitin and change its solubility leading to progressive aggregation and toxicity. These mutations are often described as recessive disorders but increasing evidence suggests only one allele needs to be mutated to massively increase the risk of the PD. This certainly shows some evidence for it being at least a cause of PD, in addition, evidence suggests that an increase in age naturally decreases parkin solubility causing its aggregation, it would also mean that the synuclein aggregates cannot be degraded in the proteasome pathway because the E3 cannot ligate the ubiquitin. So this may be beginning to provide some insight into the formation of sporadic PD, something we still know very little about.
Oxidative stress and mitochondrial dysfunction: These are two separate mechanisms but very closely inter-related. Mitochondria are the primary cause for the generation of reactive oxygen species in cells. ROS are formed mainly through electron passage through complex I and III and the main ROS are superoxide radicals, which are one electron being added to oxygen during oxidative phosphorylation. For the most part superoxide dismutase converts it to hydrogen peroxide which is then detoxified by catalase. Unfortunately, is iron ions are present, hydrogen peroxide can be converted into hydroxyl radical due to a Fenton reaction and this molecule is highly reactive and causes massive damage in cells. Low ATP production corresponds to increased ROS level and it seems that postmortem the mitochondrial complex I has very low activity in the substantia nigra neurons suggesting a cause of PD to be a deficiency in mitochondrial complex I leading to ROS which cause cell death. It has also been found that the catalytic subunits of complex I contained oxidised proteins, correlating to decreased electron transfer, thus low ATP, increasing oxidation through complex I. this is an interesting loop and is possible, but it poses a chicken or the egg debate, how did the first oxidation occur to start this? Another question to ask is how PD mainly affects dopaminergic neurons when nearly all cells contain mitochondria.
An important thing to note is that mitochondria are more bacterial than they are eukaryotic, there is a substantial body of evidence that suggests that they are in fact prokaryotic organisms that entered eukaryotic cells millions of years ago and act in a symbiotic relationship because they produce ATP at a rapid rate and in huge numbers and they gain protection and nutrients from eukaryotic cells. This is supported by the fact their DNA is circular as in bacteria and mitochondria DNA only comes from your mother, not your father because they reproduce independently of the rest of the cell and carry their own DNA so the mitochondria from the egg reproduce rather than having genes from both parents mix to create it, which is the case with all other organelles.
Mitochondrial DNA encodes 13 proteins which are all subunits for ATP production mechanisms, it also encodes tRNA and rRNA for the protein synthesis of these genes. Mitochondria are not very big and much of the space is taken up for its function so this means that any ROS generated are always in close proximity to DNA. The close proximity accompanied by the lack of DNA protection (nucleotide excision repair, replaces damaged DNA in each cell at least 10,000 times a day but is not present in mitochondria) and no protective histones means mutations are possible and the presence of ROS makes mutations even more likely. The mutations in substantia nigra are often deletions and this type of mutation is not seen in the mitochondria in other cells like pyramidal cells, even in aged brains, suggesting that these deletions are specific to dopaminergic neurons which may then increase their susceptibility to oxidative stress, thus potentially explaining why dopaminergic neurons in the nigra are lost and not other neurons in other areas.
The final Parkinson's post will be on some of the treatments.
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