Reverse engineering Lewy bodies: how far have we come and how far can we go?

Fares, Mohamed Bilal; Jagannath, Somanath; Lashuel, Hilal A.

doi:10.1038/s41583-020-00416-6

Cited by 132 publications

(161 citation statements)

References 295 publications

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“…Ser65-phosphorylated ubiquitin (pSer65-Ub)-positive mitophagy granules were found to be accumulated in the human brain during aging and in PD patients with Lewy body disease [ 74 ]. Lewy bodies (LBs) that are α-synuclein-rich cytosolic inclusions serve as a pathological hallmark of PD and many other neurodegenerative diseases [ 120 ]. LB-like inclusions often trap fragmented membranes, vesicular structures, and organelles (mitochondria, autophagosomes, and lysosomes), and impair pathways of protein degradation or mitochondrial homeostasis [ 120 ].…”

Section: Mitochondrial Quality Control At Multiple Levelsmentioning

confidence: 99%

“…Lewy bodies (LBs) that are α-synuclein-rich cytosolic inclusions serve as a pathological hallmark of PD and many other neurodegenerative diseases [ 120 ]. LB-like inclusions often trap fragmented membranes, vesicular structures, and organelles (mitochondria, autophagosomes, and lysosomes), and impair pathways of protein degradation or mitochondrial homeostasis [ 120 ]. In addition, pSer65-Ub were increased in brain tissue of mice model lacking PARKIN and bearing mutations in POLG (the catalytic subunit of the mitochondrial DNA polymerase gamma), which leads to mitochondrial dysfunction as a result of mtDNA mutations, premature aging, and defective respiratory chain assembly [ 121 ].…”

Section: Mitochondrial Quality Control At Multiple Levelsmentioning

confidence: 99%

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Common Principles and Specific Mechanisms of Mitophagy from Yeast to Humans

Kumar

Reichert

2021

IJMS

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Mitochondria are double membrane-bound organelles in eukaryotic cells essential to a variety of cellular functions including energy conversion and ATP production, iron-sulfur biogenesis, lipid and amino acid metabolism, and regulating apoptosis and stress responses. Mitochondrial dysfunction is mechanistically linked to several neurodegenerative diseases, cancer, and ageing. Excessive and dysfunctional/damaged mitochondria are degraded by selective autophagic pathways known as mitophagy. Both budding yeast and mammals use the well-conserved machinery of core autophagy-related genes (ATGs) to execute and regulate mitophagy. In mammalian cells, the PINK1-PARKIN mitophagy pathway is a well-studied pathway that senses dysfunctional mitochondria and marks them for degradation in the lysosome. PINK1-PARKIN mediated mitophagy relies on ubiquitin-binding mitophagy adaptors that are non-ATG proteins. Loss-of-function mutations in PINK1 and PARKIN are linked to Parkinson´s disease (PD) in humans, and defective mitophagy is proposed to be a main pathomechanism. Despite the common view that yeast cells lack PINK1- and PARKIN-homologs and that mitophagy in yeast is solely regulated by receptor-mediated mitophagy, some studies suggest that a ubiquitination-dependent mitophagy pathway also exists. Here, we will discuss shared mechanisms between mammals and yeast, how mitophagy in the latter is regulated in a ubiquitin-dependent and -independent manner, and why these pathways are essential for yeast cell survival and fitness under various physiological stress conditions.

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Section: Mitochondrial Quality Control At Multiple Levelsmentioning

confidence: 99%

Section: Mitochondrial Quality Control At Multiple Levelsmentioning

confidence: 99%

Common Principles and Specific Mechanisms of Mitophagy from Yeast to Humans

Kumar

Reichert

2021

IJMS

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“…Lewy pathology with α-syn aggregation was found to be cellular toxic, by inducing multiple neuronal dysfunctions such as mitochondrial deficiency ( Vekrellis et al, 2011 ; Fares et al, 2021 ). The development of Lewy pathology in the originally healthy grafted neurons might lead to their early degeneration, therefore causing the gradual loss of GIBs.…”

Section: Structure and Function Interplay Of The Grafted Neuronsmentioning

confidence: 99%

“…Therefore, modulating α-syn aggregation in grafted cells may decelerate the Lewy pathology formation. As the toxic species of are mainly the aggregated forms such as oligomers and fibrils ( Lashuel et al, 2013 ; Fares et al, 2021 ), conformation-specific antibodies which binds to certain species of α-syn, therefore, inhibit the aggregation initiation and progression. Several antibody treatments have been proven effective ( De Genst et al, 2010 ), some of which have already moved on to clinical trial phase, after proven effective in preventing formation of aggregates or deattenuate the misfolded α-syn ( Krishnan et al, 2014 ).…”

Section: Lessons We Learned From the Autopsy Studies—how To Improve Transplantation Therapymentioning

confidence: 99%

Postmortem Studies of Fetal Grafts in Parkinson’s Disease: What Lessons Have We Learned?

2021

Front. Cell Dev. Biol.

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Neural transplantation is a potential therapeutic method for Parkinson’s disease (PD). Fetal dopaminergic (DA) neurons have been important transplantation cell sources in the history of replacement therapy for PD. Several decades of preclinical animal experiments and clinical trials using fetal DA neuron transplantation in PD therapy have shown not only promising results but also problems. In order to reveal possible factors influencing the clinical outcomes, we reviewed fetal DA neuron transplantation therapies from 1970s to present, with a special focus on postmortem studies. Firstly, we gave a general description of the clinical outcomes and neuroanatomy of grafted cases; secondly, we summarized the main available postmortem studies, including the cell survival, reinnervation, and pathology development. In the end, we further discussed the link between function and structure of the grafts, seeking for the possible factors contributing to a functional graft. With our review, we hope to provide references for future transplantation trials from a histological point of view.

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“…Until recently it was believed that misfolded fibrillar α-syn is the main component of LBs [4]. Surprisingly, a recent report found that LBs are mostly composed of membrane fragments, organelles, vesicular structures, and various lipid constituencies [5].…”

Section: Introductionmentioning

confidence: 99%

Can the lack of fibrillar form of alpha-synuclein in Lewy bodies be explained by its catalytic activity?

2021

Preprint

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Finding the causative pathophysiological mechanisms for Parkinson's disease (PD) is important for developing therapeutic interventions. Until recently, it was believed that Lewy bodies (LBs), the hallmark of PD, are mostly composed of alpha-synuclein (α-syn) fibrils. Recent results (Shahmoradian et al., Lewy pathology in Parkinson's disease consists of crowded organelles and lipid membranes, Nature Neuroscience 22 (2019) 1099-1109) demonstrated that the fibrillar form of α-syn is lacking from LBs. Here we propose that this surprising observation can be explained by the catalytic activity of the fibrillar form of α-syn. We assumed that α-syn fibrils catalyze the formation of LBs, but do not become part of them. We developed a mathematical model based on this hypothesis. By using the developed model, we investigated the consequences of this hypothesis. In particular, the model suggests that the long incubation time of PD can be explained by a two-step aggregation process that leads to its development: (i) aggregation of monomeric α-syn into α-syn oligomers and fibrils and (ii) clustering of membrane-bound organelles, which may cause disruption of axonal trafficking and lead to neuron starvation and death. The model shows that decreasing the rate of destruction of α-syn aggregates in somatic lysosomes accelerates the formation of LBs. Another consequence of the model is the prediction that removing α-syn aggregates from the brain after the aggregation of membrane-bound organelles into LBs has started may not stop the progression of PD because LB formation is an autocatalytic process; hence, the formation of LBs will be catalyzed by aggregates of membrane-bound organelles even in the absence of α-syn aggregates. The performed sensitivity study made it possible to establish the hierarchy of model parameters with respect to their effect on the formation of vesicle aggregates in the soma.

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Reverse engineering Lewy bodies: how far have we come and how far can we go?

Cited by 132 publications

References 295 publications

Common Principles and Specific Mechanisms of Mitophagy from Yeast to Humans

Common Principles and Specific Mechanisms of Mitophagy from Yeast to Humans

Postmortem Studies of Fetal Grafts in Parkinson’s Disease: What Lessons Have We Learned?

Can the lack of fibrillar form of alpha-synuclein in Lewy bodies be explained by its catalytic activity?

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