Altered ceramide metabolism is a feature in the extracellular vesicle-mediated spread of alpha-synuclein in Lewy body disorders

Kurzawa‐Akanbi, Marzena; Tammireddy, Seshu R.; Fabrik, Ivo; Gliaudelytė, Lina; Doherty, Mary K.; Heap, Rachel E.; Matečko-Burmann, Irena; Burmann, Björn M.; Trost, Matthias; Lucocq, John M.; Gherman, Anda; Fairfoul, Graham; Singh, Preeti; Burté, Florence; Green, Alison; McKeith, Ian; Härtlová, Anetta; Whitfield, Phillip D.; Morris, Christopher M.

doi:10.1007/s00401-021-02367-3

Cited by 41 publications

(45 citation statements)

References 95 publications

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“…GCase is an enzyme that hydrolyzes glucosylceramide (GlcCer) and glucosylsphingosine (GlcSph) into glucose and ceramide or sphingosine, respectively [ 64 ]. CSF GCase activity has been shown to be significantly reduced in PD as well as in DLB compared to controls [ 65 , 66 , 67 , 68 , 69 , 70 ].…”

Section: Lysosomal Biomarkersmentioning

confidence: 99%

Update on CSF Biomarkers in Parkinson’s Disease

et al. 2022

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Progress in developing disease-modifying therapies in Parkinson’s disease (PD) can only be achieved through reliable objective markers that help to identify subjects at risk. This includes an early and accurate diagnosis as well as continuous monitoring of disease progression and therapy response. Although PD diagnosis still relies mainly on clinical features, encouragingly, advances in biomarker discovery have been made. The cerebrospinal fluid (CSF) is a biofluid of particular interest to study biomarkers since it is closest to the brain structures and therefore could serve as an ideal source to reflect ongoing pathologic processes. According to the key pathophysiological mechanisms, the CSF status of α-synuclein species, markers of amyloid and tau pathology, neurofilament light chain, lysosomal enzymes and markers of neuroinflammation provide promising preliminary results as candidate biomarkers. Untargeted approaches in the field of metabolomics provide insights into novel and interconnected biological pathways. Markers based on genetic forms of PD can contribute to identifying subgroups suitable for gene-targeted treatment strategies that might also be transferable to sporadic PD. Further validation analyses in large PD cohort studies will identify the CSF biomarker or biomarker combinations with the best value for clinical and research purposes.

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Section: Lysosomal Biomarkersmentioning

confidence: 99%

Update on CSF Biomarkers in Parkinson’s Disease

et al. 2022

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“…Sporadic PD patients also have altered levels of glucosylceramide and ceramide, the substrate and product of GCase enzyme activity (Mielke et al, 2013 ; Guedes et al, 2017 ), further supporting the observation that GBA enzymatic dysfunction is not a prerequisite for ceramide accumulation. EVs isolated from PD patient brain tissue were found to have increased levels of membranous ceramides that increased binding affinity for α-syn, leading to increased α-syn accumulation, aggregation, and propagation (Kurzawa-Akanbi et al, 2021 ). These studies suggest that reduced GCase activity and the resulting alterations in lipid metabolism are critical in the pathogenic process causing PD.…”

Section: Lipid Metabolism In Neurodegenerationmentioning

confidence: 99%

“…The reduction of ceramide, which is critical for ESCRT-independent exosome release, with inhibition of neutral sphingomyelinase 2 (nSMase2) reduced the spread of α-syn among co-cultured SH-SY5Y cells (Sackmann et al, 2019 ). A recent study of brain tissue and CSF of patients with PD or DLB with and without GBA mutations found that there was a significant increase in several ceramide species in brain tissue and EVs isolated from CSF from all disease patients compared to control, independent of GBA genotype (Kurzawa-Akanbi et al, 2021 ). Interestingly, proteomic analysis revealed the presence of α-syn, β-syn, gamma-syn, and tau in both disease and control EVs, with no significant difference in levels between either group.…”

Section: Lipid Alterations Influencing Exosomes and Progression Of Neurodegenerationmentioning

confidence: 99%

“…Interestingly, proteomic analysis revealed the presence of α-syn, β-syn, gamma-syn, and tau in both disease and control EVs, with no significant difference in levels between either group. However, wild-type α-syn monomers were observed to bind much more readily to disease EVs than control EVs, and this interaction resulted in fibrillization of α-syn, which was absent in the presence of control EVs (Kurzawa-Akanbi et al, 2021 ). Although it was surprising that the presence of disease rather than GBA genotype was associated with α-syn aggregation, lipid alterations, and α-syn-EV interactions, this study interrogated post-mortem tissues from presumably end-stage disease, where the effect of GBA genotype may not be as strong as early and mid-stage disease.…”

Section: Lipid Alterations Influencing Exosomes and Progression Of Neurodegenerationmentioning

confidence: 99%

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Lipid Metabolism Influence on Neurodegenerative Disease Progression: Is the Vehicle as Important as the Cargo?

Estes

Lin

Khera

et al. 2021

Front. Mol. Neurosci.

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Many neurodegenerative diseases are characterized by abnormal protein aggregates, including the two most common neurodegenerative diseases Alzheimer’s disease (AD) and Parkinson’s disease (PD). In the global search to prevent and treat diseases, most research has been focused on the early stages of the diseases, including how these pathogenic protein aggregates are initially formed. We argue, however, that an equally important aspect of disease etiology is the characteristic spread of protein aggregates throughout the nervous system, a key process in disease progression. Growing evidence suggests that both alterations in lipid metabolism and dysregulation of extracellular vesicles (EVs) accelerate the spread of protein aggregation and progression of neurodegeneration, both in neurons and potentially in surrounding glia. We will review how these two pathways are intertwined and accelerate the progression of AD and PD. Understanding how lipid metabolism, EV biogenesis, and EV uptake regulate the spread of pathogenic protein aggregation could reveal novel therapeutic targets to slow or halt neurodegenerative disease progression.

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“…103 More recently, Morris and colleagues revealed that Lewy body disorders extracellular vesicles constitute a “pathological package” that is capable of inducing aggregation of wild‐type alpha‐synuclein. 104 …”

Section: The Roles Of Exs In Cns Injury Diseasesmentioning

confidence: 99%

The promise of exosome applications in treating central nervous system diseases

Mattingly

Bihl

et al. 2021

CNS Neurosci Ther

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Exosomes (EXs) are a major type of extracellular vesicles released by cells highly conserved from microorganisms to mammals. 1 Their size ranges from 20 to 150 nm in diameter. About 50 years ago, they were initially considered cellular "waste." In the early 1980s, EXs were recognized as distinct entities. Later in 1987, the term "exosome" was coined for these membrane particles. Over the past decades, increasing evidence shows that EXs can cross the blood-brain barrier (BBB) and serve cell-to-cell communicators via conveying their carried biological cargoes (nuclear acids, proteins, and lipids). 2,3 In the central nervous system (CNS), EXs are released from virtually all brain cells, including neurons, astrocytes, microglia, and endothelial cells., 4,5 and exchange molecule messages related to neuronal function and neurotransmission in the brain via the reciprocal communication between brain cells.Given the capability of EXs to reach body compartments and connect origin cells with target cells, EXs have a promising potential to be used in clinical applications. Indeed, a large body of preclinical studies has shown the implication and therapeutic potential of EXs in CNS diseases. Here, we review the current state of the knowledge of EXs, the roles and applications of EXs as a viable pathological biomarker, and EX-based therapy for CNS diseases. | OVERVIE W OF E X S | EX biogenesis, isolation, and contentsEX generation is initiated by a process that involves double invagination of the plasma membrane and the formation of intracellular multivesicular bodies (MVBs). The MVBs contain intraluminal vesicles that are secreted as EXs via exocytosis and MVB fusion to the plasma membrane. 6,7 Although the exact biogenesis mechanism has not been fully delineated, multiple molecules including Ras-related

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Altered ceramide metabolism is a feature in the extracellular vesicle-mediated spread of alpha-synuclein in Lewy body disorders

Cited by 41 publications

References 95 publications

Update on CSF Biomarkers in Parkinson’s Disease

Update on CSF Biomarkers in Parkinson’s Disease

Lipid Metabolism Influence on Neurodegenerative Disease Progression: Is the Vehicle as Important as the Cargo?

The promise of exosome applications in treating central nervous system diseases

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