Parkinson's disease (PD) is a neurodegenerative disorder characterized by a classical triad of motor symptoms. The main focus of this disease is on the progressive degeneration of the dopaminergic neurons in the substantia nigra pars compacta. Although this pathology may explain the motor symptoms it is not thought to underlie other, non-motor, symptoms associated with PD. The pathology is not restricted to the substantia nigra, also other regions of the brain are affected .
The neurons in affected regions exhibit abnormal cytoplasmic protein inclusions that are named Lewy bodies (LB) and Lewy neuritis (LN), which are protein aggregates localized in the cell body or neuronal processes, respectively [1,2]. The main component of these aggregates is Î±-synuclein. This natively unfolded protein is known to be present in nerve terminals and it has been suggested to play a role in vesicular transport [1,3]. The Î±-synuclein in LBs and LNs is misfolded and evidence points to this protein as a key player to the pathogenesis of PD. Although it is unclear what the roles of LBs and LNs are, mutations in the Î±-synuclein gene underlie rare, inherited forms of PD [2,3].
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The pattern by which LBs and LNs appear in the brain is intensively studied and it has been proposed that PD progresses in six stages. During the first stages of the disease the patients develop non-motor problems due to deposits of misfolded Î±-synuclein in the motor vagus nerve and olfactory bulb, among other regions of the nervous system. This is called the presymptomatic phase because of the absence of motor problems. In the next stages the motor function declines and in the advanced stages impaired cognitive functioning appears [3,4].
Currently, the patients have to rely on treatment that gives them partial relief of these symptoms, but without affecting the deterioration of brain functions . Another, more viable, therapeutic strategy is based on a concept that new dopaminergic neurons can replace those that are lost in PD. Recently, patients who survived for more than ten years after initial fetal nigral transplantations have come to autopsy. It was shown that the transplanted neurons underwent the same pathological changes as seen in PD. Studying the mechanisms by which the disease spreads to the healthy graft may provide insight into the understanding of how Î±-synuclein pathology spreads in PD .
Summary of seminar
The biggest risk factor of PD is age. The average age of individuals who start showing the first symptoms is about 50-60 years old. The disease has a progressive course and is characterized by slowness of movements, stiffness and tremor. Up till 15 years ago these three symptoms were the hallmark of PD. However, it is now known to cause many more problems during the early stages of the disease, such as sleep disorders, dementia and constipation.
The neuropathology of PD is characterized by the death of midbrain dopamine neurons. In this affected part of the brain Lewy bodies are shown to be present and this indicates protein misfolding. However, the presence of Lewy bodies is not restricted to this part of the brain. The "Braak hypothesis" describes the progression of Lewy bodies starting from an initial event, such as viral infection with as entry points the vagal nerve and anterior olfactory structures. The misfolded protein then spreads via the brain stem and brain regions of the olfactory system to the midbrain area. In the terminal stage the Lewy bodies reach the neocortical areas.
In the period of 1989-1995 two patients were grafted with human donor tissue obtained from aborted embryos. 11 and 16 years after the transplantion of this nigral tissue the cases were analyzed post-mortem. Li et al and Kordower et al (2008) observed that there were Lewy bodies in some of the grafted neurons. At this point of the seminar the term "serendipity" was introduced, which means: the discovery of things which the finder was not in search of. It was shown by Chu and Kordower (2010) that cytoplasmic Î±-synuclein is accumulating in 4-year old and Î±-synuclein is aggregating in 14-year old grafts. The older the grafted neurons, the more Î±-synuclein it contains. This suggests that there is a time-dependent increase in pathology. The presence of Lewy bodies is now seen in 8 cases from 4 different surgical centers.
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There are several possible mechanisms proposed to explain how healthy-grafted neurons can develop the same pathology as the host neurons in the diseased brain. One of the mechanisms is 'permissive templating', the misfolded Î±-synuclein functions as a template for the native alfa-helix to converse in a pathogenic beta-sheet structure. It is important to establish whether and how the Î±-synuclein from the host cell is taken up by the grafted cell. The Î±-synuclein is shown to be secreted by living neurons into the extracellular fluid by exocytosis. This may be an important mechanism to spread the PD-pathology to the grafted neurons. It was demonstrated that the intracerebral injection of labeled Î±-synuclein triggers the formation of Lewy bodies. Putatively important issues for the presence of Lewy bodies in the grafted neurons are: the age of the recipient, time after grafting, inflammation, level of host Î±-synuclein expression, site of grafting and the proliferation of grafted cells.
The protein transfer of Î±-synuclein was demonstrated in cell culture models. Two cell lines were used, both expressing a different label. After 7 days there was a progressive increase in cells which expressed both labels and thus had imported Î±-synuclein. The uptake of Î±-synuclein by cells was also shown by the bimolecular fluorescence complementation technique. An important question is whether this mechanism of spreading of the protein is also relevant to other neurodegenerative diseases. This mechanism potentially provides strategies for therapeutic intervention in the progression of PD. However, it may also cause concerns for the cell transplantation therapy, because the grafted cells might succumb to PD. Parkinson-like pathology probably impairs grafted cells, but it is only partially. It has to be realized that Lewy bodies are not bad for the graft, because the recipients responded well and extended their life with 10-15 good years.
Before recent findings, it was thought that the new neurons in brains of PD patients who underwent fetal nigral transplantation are resistant to the disease process. Therefore, it seemed to offer a viable, therapeutic strategy for PD [5,6]. However, this idea was based primarily on brain autopsies of patients who had died within a few years after transplantation and modern tools to better identify classic PD pathology were not yet developed . Recent reports on post-mortem cases from PD patients who died 11 to 16 years after transplantation revealed that some grafted neurons exhibited LBs and LNs. The different findings of the old and the recent studies may be caused by differences in survival time of the patients and/or histology protocols [1,6]. Similar to the old findings, aggregated Î±-synuclein was recently not observed in patients who survived only 4 or 9 years following transplantation, suggesting that at least a decade is required for development of PD pathology in the previously healthy, grafted neurons [1,7] . This may suggest that the differences were rather related to length of the survived period after transplantation than to histology protocols.
The development of PD pathology in young, previously healthy neurons requires further consideration. Since the grafted cells were developmentally only 11-16 years old, which is far younger than the age at which nigral neurons are affected in PD, aggregation of Î±-synuclein would not be expected [6,7]. Although age is considered the biggest risk factor for PD, the young age of the grafted neurons could not protect the cells from the disease process. Therefore, aging of the dopamine neurons may not the only risk factor for disease onset . It is suggested that that development of abnormal LB structures in grafted neurons is a result of spreading of the misfolded Î±-synuclein, which is also in line with the 'Braak hypothesis' [7,8]. Several mechanisms have been proposed to explain the propagation of the PD pathology to the healthy cells, but the relative contribution of the mechanism are currently unknown . Insight from future studies will not only lead to therapeutic strategies to interfere with the course of PD, but also with other neurodegenerative diseases since a common mechanism has been proposed .
Personal highlights of the seminar
It was good that Patrik Brundin first mentioned that PD not only causes the well-known motor symptoms, but also other cognitive problems. I remembered it from previous lectures, but you easily forget because the main treatment (levodopa) is focused on relieving the motor symptoms. Thus, I was enthusiastic about the strategy to replace diseased neurons by healthy neurons as it may also restore the other problems. However, I could not sustain this enthusiasm as the seminar progressed because of the disappointing outcomes after transplantation. I could only think about how treatment provided better benefits than already obtained with the current treatment. At the end of the seminar I got my answer when Patrik Brundin emphasized that the transplant recipients did extended their lives with good years. My initial interests in this approach came back even more when it was addressed that it had revealed several mechanisms of PD pathology spread, which could lead to more effective therapies.
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