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Causes Of Death In Parkinson's Patients
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Pesticide Exposure Increases The Risk Of Developing Gene Specific And Sporadic Parkinson’s Disease Incidences
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Prion and Dementia Research Unit, Department of Neuropathology, University Medical Center Göttingen, Georg-August University Göttingen, Robert-Koch-Str. 40, Göttingen 37075, Germany
Received: 24 March 2015 / Revised: 21 May 2015 / Accepted: 1 July 2015 / Published: 16 July 2015
Locus Coeruleus Shows A Spatial Pattern Of Structural Disintegration In Parkinson’s Disease
(This article is from a special issue exploring α-Synuclein’s mechanism of cell destruction in Parkinson’s disease)
Currently, the pathophysiology of idiopathic Parkinson’s disease is explained by the loss of large dopaminergic neurons due to neurotransmitter deficiency. In the final stages of the disease, there is a loss of neurons in the substantia nigra. In addition, Lewy bodies can be found in some of the remaining neurons, which become a pathological symptom of the disease. These Lewy bodies are composed of aggregated α-synuclein, a physiological presynaptic protein. Lewy bodies are considered a pathophysiologically relevant form of α-synuclein because their appearance resembles neuron loss in the substantia nigra. Consequently, it is believed that neuron loss is the primary cause of neurodegeneration in Parkinson’s disease. Cancer, on the other hand, represents a synaptic disease. If the pathophysiology of the disease involves α-synuclein aggregation, α-synuclein pathology should be observed in synapses. As indicated, one to two orders of magnitude more α-synuclein aggregates are found in presynaptic terminals than in Lewy bodies or Lewy neurites. Degeneration of dendritic spines has been shown to be associated with synaptic α-synuclein aggregates in human disease. In experiments, using transgenic mice or cell cultures, even mild (two or three) overexpression of α-synuclein altered the localization of vesicles and reduced neurotransmitter release. Different pathways mediate these changes in the presynaptic aggregation of α-synuclein. These findings may indeed change the pathophysiological concept of Parkinson’s disease: not the loss of nerve cells, but the synaptic dysfunction of existing neurons should be the focus. From recent findings, it is clear that the death of dopaminergic neurons is a secondary event in the pathophysiology of Parkinson’s disease.
The current pathophysiological hypothesis for Parkinson’s disease is that the loss of dopaminergic neurons is the result of elimination of the neurotransmitter dopamine in the striatum, which then leads to the motor symptoms of bradykinesia, tremors, rigidity, and postural instability [1]. In Parkinson’s disease, Lewy bodies are more commonly seen in predilection areas of neuronal loss, i.e., substantia nigra and locus coeruleus. These findings are typical of the pathology seen in later stages of the disease [2]. The combination of neuron damage and Lewy bodies led to the conclusion that Lewy bodies are the pathophysiologically relevant form of α-synuclein and are responsible for the disease in association with cell death [3].
The growth of Lewy bodies in the brain of asymptomatic individuals increases with aging. This raises the question of whether Lewy bodies represent presymptomatic Parkinson’s disease, as proposed by Dixon et al. [4], or characteristic of normal aging [5]. Gibb reported an age-related increase in the number of Lewy bodies from 3.8% to 12.8% between ages six and nine. It is three to six times more common than Parkinson’s disease [6]. Several other studies show similar findings (see [7] for a review).
Juvenile Parkinson’s Disease: Disease Bioinformatics: Novus Biologicals
Patients with fewer and fewer neurons in the substantia nigra have been shown to have higher numbers of Lewy bodies than patients with severe neuronal loss, thought to be Lewy neurons dying [8]. Conversely, it has recently been shown that neuronal dysfunction and loss of nigra-neurons precede Lewy pathology [9]. Tompkins and Hill showed that substantia nigra neurons are not more likely to undergo apoptotic cell death due to the occurrence of Lewy bodies compared to the general population of substantia nigra neurons and that most neurons do not have Lewy bodies [10]. Due to dendritic abnormalities or biochemical changes, neurons are implicated in the disease process [11, 12, 13, 14].
Therefore, attempts to correlate the number of cortical or brain Lewy bodies with clinical symptoms in Parkinson’s disease and DLB have not been successful. Most studies were unable to correlate disease onset, disease duration, symptoms, visual features, hallucinations, relapse, parkinsonism severity, presence or absence of cognitive fluctuations, or cognitive decline [15, 16, 17, 18], 19]. The presence of symptoms may be related to the involvement of areas defined as measurements of Lewy bodies [20, 21, 22]. However, in a small percentage of Parkinson’s patients who develop dementia, Lewy bodies cannot be found in cortical areas or other areas outside the brain stem [23, 24]. These findings suggest that the pathophysiology of neurodegeneration and cell death cannot be explained by Lewy bodies or Lewy body-associated cell death. Lewy body formation may be a process for the detoxification of α-synuclein aggregates located in damaged cells in the neuron [ 25 ]. Localization, composition, and ultrastructure show that Lewy bodies are formed in processes related to combat and support the idea that Lewy bodies are part of protein aggregates, trying to inhibit the cell [26].
Physiologically, α-synuclein is a protein localized in presynaptic terminals. It activates N-ethylmaleimide-sensitive element attachment protein receptor (SNARE)-association as a chaperone [ 27 ], and maintains the shape of the presynaptic vesicular pool and vesicle recycling [ 28 , 29 , 30 ]. , 31]. Its role is important for neurotransmitter release [32, 33], especially dopamine [34, 35, 36, 37, 38].
The clinical symptoms of Parkinson’s disease suggest that synapse failure is the pathophysiological basis of the disease. Resting tremor, rigidity, akinesia/bradykinesia, and postural instability are the four main features of Parkinson’s disease [ 39 ]. Akinesia/bradykinesia is thought to result from impaired motor cortex activity (for review see [39]). Anxiety and rigidity are explained by nigrostriatal dopaminergic deficits. Treatment with dopamine replacement or inhibition of dopamine degradation with monoamine oxidase inhibitors has been the mainstay of treatment for Parkinson’s disease over the past century [40]. Various in vivo imaging studies of synaptic activity in the CNS have demonstrated presynaptic neurotransmitter deficits in Parkinson’s disease (reviewed in [41] ). All these findings suggest that the degenerative process in Parkinson’s disease is at the presynapse [42] and results in neurotransmitter deficiency. A delay in disease progression and a reduction in the effects of dopamine replacement therapy argue for less presynaptic growth than nerve cell death.
Mechanism Of Mir 132 3p Promoting Neuroinflammation And Dopaminergic Neurodegeneration In Parkinson’s Disease
3. A way to explain neurodegeneration in α-Synuclein aggregation disease other than Lewy bodies and cell death.
When α-synuclein aggregation is involved in the pathophysiology of disease, synapse aggregation is essential. Although the physiological form of α-synuclein is a presynaptically localized protein, α-synuclein assembly can begin in the presynapse. To test this hypothesis, we used paraffin-embedded tissue (PET) blotting, which is the simplest method known for topographic detection of protein aggregates [ 43 ]. For technical reasons, we investigated early synaptic α-synuclein pathology in cortex samples from DLB patients. As predicted by our hypothesis, we were able to detect large amounts of α-synuclein aggregates in the cortex that appeared to be much smaller than Lewy bodies. These micro-aggregates are most abundant in the cingulate cortex and their distribution is similar to that of the synaptic protein synaptophysin, indicating synaptic localization [44]. The same is observed in predilection areas in Parkinson’s disease [45] .
A problem with biochemical analysis of α-synuclein aggregates is that these aggregates cannot be solubilized [46].
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