Heterogeneity in α‐synuclein subtypes and their expression in cortical brain tissue lysates from Lewy body diseases and Alzheimer's disease

Vaikath, Nishant N.; Erskine, Daniel; Morris, Christopher M.; Majbour, Nour K.; Vekrellis, Kostas; Li, J. Y.; El-Agnaf, Omar Ali

doi:10.1111/nan.12531

Cited by 29 publications

(22 citation statements)

References 55 publications

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“…For instance, cognitive decline, sleep alterations, depression and dementia, among others are shared by a significant percentage of AD and PD patients. Moreover, amyloid deposits and intracellular phosphorylated tau and α-synuclein have been described both in AD and PD [45,85,86]. Increasing evidence points to the idea that AD can be caused by microbial infections [47,51,87] and we have provided detailed identification of fungi and bacteria in AD brains [51,53,[55][56][57].…”

Section: Discussionmentioning

confidence: 77%

Parkinson's Disease: A Comprehensive Analysis of Fungi and Bacteria in Brain Tissue

Pisa¹,

Alonso²,

Carrasco³

2020

Int. J. Biol. Sci.

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Parkinson's disease (PD) is characterized by motor disorders and the destruction of dopaminergic neurons in the substantia nigra pars compacta. In addition to motor disability, many patients with PD present a spectrum of clinical symptoms, including cognitive decline, psychiatric alterations, loss of smell and bladder dysfunction, among others. Neuroinflammation is one of the most salient features of PD, but the nature of the trigger remains unknown. A plausible mechanism to explain inflammation and the range of clinical symptoms in these patients is the presence of systemic microbial infection. Accordingly, the present study provides extensive evidence for the existence of mixed microbial infections in the central nervous system (CNS) of patients with PD. Assessment of CNS sections by immunohistochemistry using specific antibodies revealed the presence of both fungi and bacteria. Moreover, different regions of the CNS were positive for a variety of microbial morphologies, suggesting infection by a number of microorganisms. Identification of specific fungal and bacterial species in different CNS regions from six PD patients was accomplished using nested PCR analysis and next-generation sequencing, providing compelling evidence of polymicrobial infections in the CNS of PD. Most of the fungal species identified belong to the genera Botrytis, Candida, Fusarium and Malassezia. Some relevant bacterial genera were Streptococcus and Pseudomonas, with most bacterial species belonging to the phyla Actinobacteria and Proteobacteria. Interestingly, we noted similarities and differences between the microbiota present in the CNS of patients with PD and that in other neurodegenerative diseases. Overall, our observations lend strong support to the concept that mixed microbial infections contribute to or are a risk factor for the neuropathology of PD. Importantly, these results provide the basis for effective treatments of this disease using already approved and safe antimicrobial therapeutics.

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Section: Discussionmentioning

confidence: 77%

Parkinson's Disease: A Comprehensive Analysis of Fungi and Bacteria in Brain Tissue

Pisa¹,

Alonso²,

Carrasco³

2020

Int. J. Biol. Sci.

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“…We cannot rule out the possibility that LB structures devoid of fibrillar α-syn aggregates exist and could represent a rare type of α-syn pathologies in PD and synucleinopathies. Indeed, several reports have confirmed the existence of a large morphological spectrum of LBs (6,14,31,35,43,(63)(64)(65).…”

Section: Extending the Seeding Process Enabled The Reconstitution Of mentioning

confidence: 94%

The process of Lewy body formation, rather than simply α-synuclein fibrillization, is one of the major drivers of neurodegeneration

Mahul‐Mellier

Burtscher

Maharjan

et al. 2020

Proc. Natl. Acad. Sci. U.S.A.

528

551

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Parkinson’s disease (PD) is characterized by the accumulation of misfolded and aggregated α-synuclein (α-syn) into intraneuronal inclusions named Lewy bodies (LBs). Although it is widely believed that α-syn plays a central role in the pathogenesis of PD, the processes that govern α-syn fibrillization and LB formation remain poorly understood. In this work, we sought to dissect the spatiotemporal events involved in the biogenesis of the LBs at the genetic, molecular, biochemical, structural, and cellular levels. Toward this goal, we further developed a seeding-based model of α-syn fibrillization to generate a neuronal model that reproduces the key events leading to LB formation, including seeding, fibrillization, and the formation of inclusions that recapitulate many of the biochemical, structural, and organizational features of bona fide LBs. Using an integrative omics, biochemical and imaging approach, we dissected the molecular events associated with the different stages of LB formation and their contribution to neuronal dysfunction and degeneration. In addition, we demonstrate that LB formation involves a complex interplay between α-syn fibrillization, posttranslational modifications, and interactions between α-syn aggregates and membranous organelles, including mitochondria, the autophagosome, and endolysosome. Finally, we show that the process of LB formation, rather than simply fibril formation, is one of the major drivers of neurodegeneration through disruption of cellular functions and inducing mitochondria damage and deficits, and synaptic dysfunctions. We believe that this model represents a powerful platform to further investigate the mechanisms of LB formation and clearance and to screen and evaluate therapeutics targeting α-syn aggregation and LB formation.

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Section: Extending the Seeding Process Enabled The Reconstitution Of mentioning

confidence: 93%

The process of Lewy body formation, rather than simply alpha-synuclein fibrillization, is the major driver of neurodegeneration in synucleinopathies

Mahul‐Mellier

Burtscher

Maharjan

et al. 2019

Preprint

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Parkinson's disease (PD) is characterized by the accumulation of misfolded alpha-synuclein (α-syn) into intraneuronal inclusions named Lewy bodies (LB). Although it is widely believed that α-syn plays a central role in the pathogenesis of PD and synucleinopathies, the processes that govern α-syn fibrillization and LB formation in the brain remain poorly understood. In this work, we sought to reverse engineer LBs and dissect the spatiotemporal events involved in their biogenesis at the genetic, molecular, biochemical, structural, and cellular levels. Toward this goal, we took advantage of a seeding-based model of α-syn fibril formation in primary neurons and further developed this model to generate the first neuronal model that reproduces the key events leading to LB formation; including seeding, fibrillization, and the formation of LB-like inclusions that recapitulate many of the biochemical, structural, and organizational features of LBs found in post-mortem human PD brain tissues. Next, we applied an integrative approach combining confocal and correlative light-electron microscopy (CLEM) imaging methods with biochemical profiling of α-syn species and temporal proteomic and transcriptomic analyses to dissect the molecular events associated with LB formation and maturation and to elucidate their contributions to neuronal dysfunctions and neurodegeneration in PD and synucleinopathies. The results from these studies demonstrate that LB formation involves a complex interplay between α-syn fibrillization, post-translational modifications, and interactions between α-syn aggregates and membranous organelles, including mitochondria and the autophagosome and endolysosome. Furthermore, we demonstrate that the process of LB formation and maturation, rather than simply fibril formation, is the major driver of neurodegeneration through disruption of cellular functions and inducing mitochondria damage and deficits, as well as synaptic dysfunctions. Having a neuronal model that allows for unlinking of the key processes involved in LB formation is crucial for elucidating the molecular and cellular determinants of each process and their contributions to neuronal dysfunction and degeneration in PD and synucleinopathies. Such a model is essential to efforts to identify and investigate the mode of action and toxicity of drug candidates targeting α-syn aggregation and LB formation.

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Heterogeneity in α‐synuclein subtypes and their expression in cortical brain tissue lysates from Lewy body diseases and Alzheimer's disease

Cited by 29 publications

References 55 publications

Parkinson's Disease: A Comprehensive Analysis of Fungi and Bacteria in Brain Tissue

Parkinson's Disease: A Comprehensive Analysis of Fungi and Bacteria in Brain Tissue

The process of Lewy body formation, rather than simply α-synuclein fibrillization, is one of the major drivers of neurodegeneration

The process of Lewy body formation, rather than simply alpha-synuclein fibrillization, is the major driver of neurodegeneration in synucleinopathies

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