Three recent case reports (by Méndez-Guerrero et al.,Cohen et al., and Faber et al.) describe the development of acute parkinsonism following coronavirus disease 2019 (COVID-19). We discuss possible ...underlying cellular and molecular mechanisms, and whether COVID-19 might be associated with elevated long-term risk of Parkinson’s disease (PD).
Neurodegenerative diseases are commonly associated with the accumulation of intracellular or extracellular protein aggregates. Recent studies suggest that these aggregates are capable of crossing ...cellular membranes and can directly contribute to the propagation of neurodegenerative disease pathogenesis. We propose that, once initiated, neuropathological changes might spread in a 'prion-like' manner and that disease progression is associated with the intercellular transfer of pathogenic proteins. The transfer of naked infectious particles between cells could therefore be a target for new disease-modifying therapies.
Celotno besedilo
Dostopno za:
DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
Abstract Olfactory deficits are present in numerous neurodegenerative disorders and are accompanied by pathology in related brain regions. In several of these disorders, olfactory disturbances appear ...early and are considered as prodromal symptoms of the disease. In addition, pathological protein aggregates affect olfactory regions prior to other regions, suggesting that the olfactory system might be particularly vulnerable to neurodegenerative diseases. Exposed to the external environment, the olfactory epithelium and olfactory bulb allow pathogen and toxin penetration into the brain, a process that has been proposed to play a role in neurodegenerative diseases. Determining whether the olfactory bulb could be a starting point of pathology and of pathology spread is crucial to understanding how neurodegenerative diseases evolve.
We argue that pathological changes following environmental insults contribute to the initiation of protein aggregation in the olfactory bulb, which then triggers the spread of the pathology within the brain by a templating mechanism in a prion-like manner. We review the evidence for the early involvement of olfactory structures in neurodegenerative diseases and the relationship between neuropathology and olfactory function. We discuss the vulnerability and putative underlying mechanisms by which pathology could be initiated in the olfactory bulb, from the entry of pathogens (promoted by increased permeability of the olfactory epithelium with aging or inflammation) to the sensitivity of the olfactory system to oxidative stress and inflammation. Finally, we review changes in protein expression and neural excitability triggered by pathogenic proteins that can promote pathogenesis in the olfactory bulb and beyond.
Starting two decades ago with the discoveries of genetic links between alpha-synuclein and Parkinson's disease risk and the identification of aggregated alpha-synuclein as the main protein ...constituent of Lewy pathology, alpha-synuclein has emerged as the major therapeutic target in Parkinson's disease and related synucleinopathies. Following the suggestion that alpha-synuclein pathology gradually spreads through the nervous system following a stereotypic pattern and the discovery that aggregated forms of alpha-synuclein can propagate pathology from one cell to another, and thereby probably aggravate existing deficits as well as generate additional symptoms, the idea that alpha-synuclein is a viable therapeutic target gained further support. In this review we describe current challenges and possibilities with alpha-synuclein as a therapeutic target. We briefly highlight gaps in the knowledge of the role of alpha-synuclein in disease, and propose that a deeper understanding of the pathobiology of alpha-synuclein can lead to improved therapeutic strategies. We describe several treatment approaches that are currently being tested in advanced animal experiments or already are in clinical trials. We have divided them into approaches that reduce alpha-synuclein production; inhibit alpha-synuclein aggregation inside cells; promote its degradation either inside or outside cells; and reduce its uptake by neighbouring cells following release from already affected neurons. Finally, we briefly discuss challenges related to the clinical testing of alpha-synuclein therapies, for example difficulties in monitoring target engagement and the need for relatively large trials of long duration. We conclude that alpha-synuclein remains one of the most compelling therapeutic targets for Parkinson's disease, and related synucleinopathies, and that the multitude of approaches being tested provides hope for the future.
Cancer enzyme affects Parkinson's disease Brundin, Patrik; Wyse, Richard
Science (American Association for the Advancement of Science),
11/2018, Letnik:
362, Številka:
6414
Journal Article
Recenzirano
New insights identify a possible target for slowing neurodegeneration
Parkinson's disease (PD) is a progressive neurodegenerative disease characterized by rigidity, tremor, and slowness of movement, ...as well as a wide range of debilitating nonmotor symptoms (
1
). The neuropathology is characterized by loss of midbrain dopamine–producing neurons and the occurrence of intraneuronal protein aggregates, largely comprising the protein α-synuclein, that are distributed widely throughout the nervous system. Current treatments are focused on alleviating the impaired movement, and there is no therapy that slows PD progression. With almost 7 million patients worldwide, finding ways to prevent long-term neurodegeneration in PD and slow disease progression are vital goals. On page 557 of this issue, Kam
et al.
(
2
) describe a new molecular pathway that could explain why α-synuclein aggregates form in PD. Moreover, their findings suggest a pharmacological approach to slowing PD progression.
In Parkinson's disease, some of the first alpha-synuclein aggregates appear in the olfactory system and the dorsal motor nucleus of the vagus nerve before spreading to connected brain regions. We ...previously demonstrated that injection of alpha-synuclein fibrils unilaterally into the olfactory bulb of wild type mice leads to widespread synucleinopathy in brain regions directly and indirectly connected to the injection site, consistently, over the course of periods longer than 6 months. Our previously reported observations support the idea that alpha-synuclein inclusions propagates between brain region through neuronal networks. In the present study, we further defined the pattern of propagation of alpha-synuclein inclusions and developed a mathematical model based on known mouse brain connectivity. Using this model, we first predicted the pattern of alpha-synuclein inclusions propagation following an injection of fibrils into the olfactory bulb. We then analyzed the fitting of these predictions to our published histological data. Our results demonstrate that the pattern of propagation we observed in vivo is consistent with axonal transport of alpha-synuclein aggregate seeds, followed by transsynaptic transmission. By contrast, simple diffusion of alpha-synuclein fits very poorly our in vivo data. We also found that the spread of alpha-synuclein inclusions appeared to primarily follow neural connections retrogradely until 9 months after injection into the olfactory bulb. Thereafter, the pattern of spreading was consistent with anterograde propagation mathematical models. Finally, we applied our mathematical model to a different, previously published, dataset involving alpha-synuclein fibril injections into the striatum, instead of the olfactory bulb. We found that the mathematical model accurately predicts the reported progressive increase in alpha-synuclein neuropathology also in that paradigm. In conclusion, our findings support that the progressive spread of alpha-synuclein inclusions after injection of protein fibrils follows neural networks in the mouse connectome.
•Mathematically modeling αsyn spread along fiber tracts recreates inclusions patterns.•Modeled retrograde (post-to-presynaptic) spread best recreates early inclusions patterns.•Modeled anterograde (pre-to-postsynaptic) spread better fits later inclusions pattern.•Overall results indicate a potential directional switch in αsyn spread over time.•All above results are consistent across multiple, independently collected, datasets.
The pathogenesis of Parkinson's disease (PD) involves the accumulation of aggregated α-synuclein, which has been suggested to begin in the gastrointestinal tract. Here, we determined the capacity of ...the appendix to modify PD risk and influence pathogenesis. In two independent epidemiological datasets, involving more than 1.6 million individuals and over 91 million person-years, we observed that removal of the appendix decades before PD onset was associated with a lower risk for PD, particularly for individuals living in rural areas, and delayed the age of PD onset. We also found that the healthy human appendix contained intraneuronal α-synuclein aggregates and an abundance of PD pathology-associated α-synuclein truncation products that are known to accumulate in Lewy bodies, the pathological hallmark of PD. Lysates of human appendix tissue induced the rapid cleavage and oligomerization of full-length recombinant α-synuclein. Together, we propose that the normal human appendix contains pathogenic forms of α-synuclein that affect the risk of developing PD.
Parkinson's disease is a progressive neurological disorder that is characterized by the formation of intracellular protein inclusion bodies composed primarily of a misfolded and aggregated form of ...the protein α‐synuclein. There is growing evidence that supports the prion‐like hypothesis of α‐synuclein progression. This hypothesis postulates that α‐synuclein is a prion‐like pathological agent and is responsible for the progression of Parkinson pathology in the brain. Potential misfolding or aggregation of α‐synuclein that might occur in the peripheral nervous system as a result of some insult, environmental or genetic (or more likely a combination of both) that might spread into the midbrain, eventually causing degeneration of the neurons in the substantia nigra. As the disease progresses further, it is likely that α‐synuclein pathology continues to spread throughout the brain, including the cortex, leading to deterioration of cognition and higher brain functions. While it is unknown why α‐synuclein initially misfolds and aggregates, a great deal has been learned about how the cell handles aberrant α‐synuclein assemblies. In this review, we focus on these mechanisms and discuss them in an attempt to define the role that they might play in the propagation of misfolded α‐synuclein from cell‐to‐cell.
The prion‐like hypothesis of α‐synuclein pathology suggests a method for the transmission of misfolded α‐synuclein from one neuron to another. This hypothesis postulates that misfolded α‐synuclein becomes aggregation prone and when released and taken up by neighboring cells, seeds further misfolding and aggregation. In this review we examine the cellular mechanisms that are involved in the processing of α‐synuclein and how these may contribute to the prion‐like propagation of α‐synuclein pathology.
This article is part of a special issue on Parkinson disease.
The prion‐like hypothesis of α‐synuclein pathology suggests a method for the transmission of misfolded α‐synuclein from one neuron to another. This hypothesis postulates that misfolded α‐synuclein becomes aggregation prone and when released and taken up by neighboring cells, seeds further misfolding and aggregation. In this review we examine the cellular mechanisms that are involved in the processing of α‐synuclein and how these may contribute to the prion‐like propagation of α‐synuclein pathology.
This article is part of a special issue on Parkinson disease.
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