Dual effects of β-synuclein on the pathogenesis of Parkinson disease (original) (raw)
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The aggregation of alpha synuclein (a-syn) is a neuropatho-logical feature that defines a spectrum of disorders collectively termed synucleinopathies, and of these, Parkinson's disease (PD) is arguably the best characterized. Aggregated a-syn is the primary component of Lewy bodies, the defining pathological feature of PD, while mutations or multiplications in the a-syn gene result in familial PD. The high correlation between a-syn burden and PD has led to the hypothesis that a-syn aggregation produces toxicity through a gain-of-function mechanism. However, a-syn has been implicated to function in a diverse range of essential cellular processes such as the regulation of neurotransmission and response to cellular stress. As such, an alternative hypothesis with equal explanatory power is that the aggregation of a-syn results in toxicity because of a toxic loss of necessary a-syn function, following sequestration of functional forms a-syn into insoluble protein aggregates. Within this review, we will provide an overview of the literature linking a-syn to PD and the knowledge gained from current a-syn-based animal models of PD. We will then interpret these data from the viewpoint of the a-syn loss-of-function hypothesis and provide a potential mechanistic model by which loss of a-syn function could result in at least some of the neurodegeneration observed in PD. By providing an alternative perspective on the etiopathogenesis of PD and synucleinopathies, this may reveal alternative avenues of research in order to identify potential novel therapeutic targets for disease modifying strategies.
Potential role of α-synuclein in neurodegeneration: studies in a rat animal model
Journal of Neurochemistry, 2012
The synucleins are abundant proteins that are predominantly expressed in neurons throughout the mammalian system. The major synuclein proteins expressed in the central nervous system (CNS), a-synuclein (a-syn), b-synuclein (b-syn), and c-synuclein (c-syn), are localized predominantly in presynaptic terminals and the nucleus. They are small (127-140 amino acids) natively soluble unfolded proteins, which are highly charged and have low hydropathy Brice 2000, Norris et al. 2004). A recent publication suggests that a-syn occurs physiologically as a helically folded tetramer that resists aggregation (Bartels et al. 2011). The findings of Bartels et al. (2011) were confirmed by Wang et al. (2011), while others described a-syn as a disordered monomer Abstract
Β-Synuclein Aggregates and Induces Neurodegeneration in Dopaminergic Neurons
Annals of Neurology, 2013
Objective: Whereas the contribution of a-synuclein to neurodegeneration in Parkinson disease is well accepted, the putative impact of its close homologue, b-synuclein, is enigmatic. b-Synuclein is widely expressed throughout the central nervous system, as is a-synuclein, but the physiological functions of both proteins remain unknown. Recent findings have supported the view that b-synuclein can act as an ameliorating regulator of a-synuclein-induced neurotoxicity, having neuroprotective rather than neurodegenerative capabilities, and being nonaggregating due to the absence of most of the aggregation-promoting NAC domain. However, a mutation of b-synuclein linked to dementia with Lewy bodies rendered the protein neurotoxic in transgenic mice, and fibrillation of b-synuclein has been demonstrated in vitro. Methods: Neurotoxicity and aggregation properties of a-, band nd c-synuclein were comparatively elucidated in the rat nigro-striatal projection and in cultured neurons. Results: Supporting the hypothesis that b-synuclein can act as a neurodegeneration-inducing factor, we demonstrated that wild-type b-synuclein is neurotoxic for cultured primary neurons. Furthermore, b-synuclein formed proteinase K-resistant aggregates in dopaminergic neurons in vivo, leading to pronounced and progressive neurodegeneration in rats. Expression of b-synuclein caused mitochondrial fragmentation, but this fragmentation did not render mitochondria nonfunctional in terms of ion handling and respiration even at late stages of neurodegeneration. A comparison of the neurodegenerative effects induced by a-, band nd c-synuclein revealed that b-synuclein was eventually as neurotoxic as a-synuclein for nigral dopaminergic neurons, whereas c-synuclein proved to be nontoxic and had very low aggregation propensity. Interpretation: Our results suggest that the role of b-synuclein as a putative modulator of neuropathology in aggregopathies like Parkinson disease and dementia with Lewy bodies needs to be revisited.
Role of a-Synuclein in Cell Biology: A Hypothesis and its Implications in Neurodegenerative Diseases
2022
I wish to suggest a physiological function for alpha-synuclein (a-syn) that has the potential to explain its role in pathology. Intraneuronal proteinaceous Lewy Bodies (LBs), the pathological hallmark of Parkinson’s disease and other synucleinopathies, consist majorly of a-syn. Ample evidence suggests that LBs are not the result of simple amyloidosis of cytosolic a-syn. Benign soluble unstructured a-syn gets converted into toxic species which preferentially accumulates in LBs. But how these aberrant a-syn molecules are produced in the cytosol, is still not clear. The present hypothesis is an effort to relate a metabolic reaction specific to neuronal function, that is, phase transition, with the pathobiology of a-syn. During high frequency stimulation, which entails rapid phase transition reactions at the presynaptic compartment, aberrant interaction of a-syn with the membrane occasionally generates toxic a-syn molecules. My conjecture is that the physiological function of a-syn is t...
Proceedings of the National Academy of Sciences, 2005
Abnormal biology of ␣-synuclein (␣-Syn) is directly implicated in the pathogenesis of Parkinson's disease and other ␣-synucleinopathies. Herein, we demonstrate that C-terminally truncated ␣-Syn (␣-Syn⌬C), enriched in the pathological ␣-Syn aggregates, is normally generated from full-length ␣-Syn independent of ␣-Syn aggregation in brains and in cultured cells. The accumulation of ␣-Syn⌬C is enhanced in neuronal cells as compared with nonneuronal cells. Significantly, the expression of familial Parkinson's disease-linked mutant ␣-Syn is associated with the enhanced cellular accumulation of ␣-Syn⌬C. Moreover, substoichiometric amounts of ␣-Syn⌬C enhance the in vitro aggregation of the more abundant full-length ␣-Syn. Finally, cases of ␣-synucleinopathy exhibit increases in the total soluble ␣-Syn and a higher proportion of soluble ␣-Syn⌬C, a condition favoring the aggregation of ␣-Syn.
A β-synuclein mutation linked to dementia produces neurodegeneration when expressed in mouse brain
Nature Communications, 2010
The discovery of α-synuclein (αs) mutations has made a major contribution to the understanding of the pathogenesis of α-synucleinopathies such as Parkinson's disease and dementia with Lewy bodies (DLB). In contrast, less attention has been paid to β-synuclein (βs) mutations. In this paper, we show that transgenic (tg) mice expressing DLB-linked P123H βs develop progressive neurodegeneration, as characterized by axonal swelling, astrogliosis and behavioural abnormalities, with memory disorder being more prominent than motor deficits. Furthermore, cross-breeding of P123H βs tg mice with αs tg mice, but not with αs knockout mice, greatly enhanced neurodegeneration phenotypes. These results suggest that P123H βs is pathogenic and cooperates with pathogenic αs to stimulate neurodegeneration in mouse brain, indicating a causative role of P123H βs in familial DLB. Given the neuritic pathology of βs in sporadic α-synucleinopathies, it appears that alteration of βs can contribute to the pathogenesis of a broad range of α-synucleinopathies.
Nature Communications, 2010
The discovery of α-synuclein (αS) mutations has made a major contribution to the understanding of the pathogenesis of α-synucleinopathies such as Parkinson's disease and dementia with Lewy bodies (DLB). In contrast, less attention has been paid to β-synuclein (βS) mutations. In this paper, we show that transgenic (tg) mice expressing DLB-linked P123H βS develop progressive neurodegeneration, as characterized by axonal swelling, astrogliosis and behavioural abnormalities, with memory disorder being more prominent than motor deficits. Furthermore, cross-breeding of P123H βS tg mice with αS tg mice, but not with αS knockout mice, greatly enhanced neurodegeneration phenotypes. These results suggest that P123H βS is pathogenic and cooperates with pathogenic αS to stimulate neurodegeneration in mouse brain, indicating a causative role of P123H βS in familial DLB. Given the neuritic pathology of βS in sporadic α-synucleinopathies, it appears that alteration of βS can contribute to the pathogenesis of a broad range of α-synucleinopathies.
Functionally different α-synuclein inclusions yield insight into Parkinson’s disease pathology
Scientific Reports, 2016
The formation of α-synuclein (α-S) amyloid aggregates, called Lewy bodies (LBs), is a hallmark of Parkinson's disease (PD). The function of LBs in the disease process is however still unclear; they have been associated with both neuroprotection and toxicity. To obtain insight into this contradiction, we induced the formation of α-S inclusions, using three different induction methods in SH-SY5Y cells and rat-derived primary neuronal cells. Using confocal and STED microscopy we observed inductiondependent differences in α-S inclusion morphology, location and function. The aggregation of α-S in functionally different compartments correlates with the toxicity of the induction method measured in viability assays. The most cytotoxic treatment largely correlates with the formation of proteasomeassociated, juxta-nuclear inclusions. With less toxic methods cytosolic deposits that are not associated with the proteasome are more prevalent. The distribution of α-S over at least two different types of inclusions is not limited to cell models, but is also observed in primary neuronal cells and in human mesencephalon. The existence of functionally different LBs, in vivo and in vitro, gives important insights in the impact of Lewy Body formation on neuronal functioning and may thereby provide a platform for discovering therapeutics. The aggregation of soluble proteins into insoluble, β-sheet-rich amyloid fibrils is characteristic for many neurodegenerative diseases. Intraneuronal aggregates of α-synuclein (α-S) are for example found in Parkinson's disease (PD), Lewy body dementia and multiple system atrophy 1-3. Whereas extracellular β-amyloid deposits and intracellular accumulations of phosphorylated tau protein occur in Alzheimer's disease 4,5. In Huntington's disease, polyglutamine-expanded huntingtin (htt) protein accumulates within intranuclear inclusion bodies or neurites 6 and in amyotrophic lateral sclerosis, motor neurons develop protein-rich inclusions containing superoxide dismutase 1, TAR DNA-binding protein 43 or the RNA-binding protein fused-in-sarcoma in their cell bodies and axons 7-10. In PD, α-S amyloid inclusions such as Lewy neurites (LN) and Lewy bodies (LB) can be found in neurons and glia cells 2,3,11. The topographical progression of neuronal death, and the development of α-S immunoreactive Lewy body related structures 12,13 , here abbreviated to Lewy body like inclusions (LBLI), throughout the brain is used to stage PD pathology 14. The pathologically determined stages are in many cases related to clinical features observed in patients 15. Nevertheless, the role of LBLI during the progression of PD is unclear. LBLI may be indicative of cellular dysfunction and death 16,17 but have also been described as harmless, inert or neuroprotective protein aggregates 18. PD symptoms have been shown to directly correlate with the density of neurons in the substantia nigra pars compacta 19 , but no correlation could be established between the number of LBLI and the severity of disease symptoms 16. Assuming LBLI are indeed inert, one would expect the affected cells to have a normal life span. With the loss of other cells in the tissue 19 , the proportion of cells with LBLI should therefore