This article comes from: Parkinson's and prion - xupenggoing article - know almost https://zhuanlan.zhihu.com/p/58344405
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Finishing original logic:
Lewy bodies is a protein aggregates, are typical signs of Parkinson's disease. Lewy body pathology may be diffused to the transplanted tissue from the host.
SNCA gene (encoding alpha] -synuclein α-synuclein) is one of the causes of hereditary Parkinson disease [3]; α- synuclein is a major component of Lewy bodies [4] => established Lewy the link between body and Parkinson's disease.
A study led by the German Goethe University anatomist Heiko Braak and Kelly Del Tredici 2003. They team with Parkinson's disease, but there are no symptoms of Parkinson's disease Lewy bodies of people dead and healthy control group were necropsied [7]. Parkinson's disease progress stepwise through the nervous system development, portion (connecting the brain and intestine connecting neurons) in the olfactory bulb and the brain stem begins, then penetrate into the brain and brainstem (including the substantia nigra region, the region may cause damage to motor symptoms), and then to the low forebrain, and finally into the cortex. This diffusion from the nose and gut to the brain stem autonomic functions of the control area, seem to explain why there will be loss of sense of smell, constipation and difficulty swallowing symptoms of impaired exercise capacity before.
But not everyone agrees that the link between Lewy bodies and neurodegenerative diseases. In fact, in some cases, Parkinson's disease neurodegeneration can occur before Lewy bodies appear. In addition, sometimes Lewy body cells, even if there is, it will not die. Researchers believe that smaller α- synuclein aggregates only the most toxic, but only in the form of Lewy bodies of reducing damage.
Jigsaw:
Some researchers even further, think what α- synuclein proliferation is not the essential reason, may just divert attention. "If diffusion only in certain cell toxicity, and no toxicity in other cells, the key factor in determining whether neuronal death must be something else, instead of α- synuclein." Northwestern University from physiology Department James Surmeier said. If the key factor is the susceptibility of neurons, we can not conclude that diffusion theory in the end to the cause of Parkinson's disease with any new insights.
Surmeier susceptibility to Parkinson's disease neurons have their own opinion. All types of affected neurons, exhibit two characteristics. They have long, highly axon branches, has a large number of synapses, it may have high levels of α- synuclein. They may also be in sustained energy and hunger active state. "The degenerate in Parkinson's disease is linked to a variety of cells is that they are living a stressful life", Surmerier said, "If these cells are more prone to α- synuclein aggregation, we would not be surprised." the problem is that it is induced by internal or external.
If a particular cell energy and waste removal systems are oppressed, then this is enough to explain the anatomical patterns of disease - inflammation gives the fatal blow. Currently the vast majority of Parkinson's disease have been identified related genes associated with mitochondrial and waste removal systems, which also support this model. All of these processes over time decay, which could also explain the age of Parkinson's disease is the largest cause of disease.
Regardless of whether α- synuclein aggregates diffusion, it is clear that it did participate in the process of Parkinson's disease. However, despite waste removal, energy production, inflammation and other processes are involved in Parkinson's disease, but did not get rid of the main villain, after all those processes are associated with α- synuclein. Sulzer team found, alpha] -synuclein react with dopamine, produces a new form of alpha] -synuclein [13], blocked important waste removal system. This also explains why dopamine neurons are more susceptible to Parkinson's disease.
"These may seem different problems, but they are closely related", Sulzer said, "We have found some how mutual cooperation between them clues, now like a jigsaw puzzle."
Important one in this puzzle associated with the diffusion theory is still not a good solution. For example, if the aggregates do move in the brain, how they are released and absorbed by the cells. "98% of the brain α- -synuclein in neurons, distributed in the cytoplasm, and not naturally secreted" , Harvard Medical School neurologist Dennis Selkoe said. In addition, Selkoe questioned whether the aggregate really diffused? Downstream really get cells from the cell material upstream of it? Or downstream cells transformed himself happened? In other words, α- synuclein aggregates diffuse it? It causes an exception? Abnormal accumulation will promote it? "My guess is that they can happen, just different situation", Sulzer said.
α- synuclein α-synuclein:
alpha] -synuclein α-synuclein: α- synuclein participating communication between neurons. Currently generally considered toxic after α- synuclein misfolding, resulting in Parkinson's disease. α- synuclein aggregates diffusion from the patient's tissue to tissue transplantation.
α- synuclein can diffuse?
A: The test-tube experiments have confirmed that misfolded forms a monomolecular α- synuclein may induce other single molecule same misfolded, these molecular clusters larger oligomers integrated, eventually forming filamentous structures called filaments (fibrils). Some of the oligomers removed from the aggregate in forming the seed, recruit more single molecule, thus speeding up the process. A need to address the core obstacle to the diffusion theory is generally considered α- synuclein is only present in the cell. This PrP and β- amyloid (culprit in Alzheimer's disease) Instead, they are present in the cell. Cell culture studies have suggested that neurons can absorb and release α- synuclein, although the mechanism is not clear.
can α- synuclein misfolding and aggregation, and may be out of the neuron. But it can spread in the brain do? In 2014, a team at the University of Barcelona will be the source of the human brain Lewy bodies injected into four monkeys in the substantia nigra and the striatum [9]. After 14 months, the researchers observed gradual degradation of neurons, first extends from the substantia nigra to the striatum long axons, followed nigra neurons themselves. Although this is a small study, but they did not report any functional changes, the first proof of Parkinson's disease brain-derived α- synuclein can trigger Parkinson's disease-like pathology in our evolutionary kin of evidence .
Prion protein (PrP) has a normal folded form, but once misfolded, may induce other normal folding of misfolded PrP - i.e. self-diffusion, ultimately leading to disease. With the proliferation of misfolded PrP, which can damage and eventually kill the cells.
references:
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