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

Marzena Kurzawa-Akanbi,Phillip D Whitfield,Björn M Burmann,Alison Green,Anda V Gherman,Irena Matečko-Burmann,Christopher M Morris,Anetta Härtlova,Ivo Fabrik,Lina Gliaudelytė,Rachel Heap,Florence Burté,Ian G Mckeith,John M Lucocq,Seshu Tammireddy,Matthias Trost,Preeti Singh,Mary K Doherty,Graham Fairfoul

doi:10.1007/s00401-021-02367-3

Abstract

Mutations in glucocerebrosidase (GBA) are the most prevalent genetic risk factor for Lewy body disorders (LBD)—collectively Parkinson’s disease, Parkinson’s disease dementia and dementia with Lewy bodies. Despite this genetic association, it remains unclear how GBA mutations increase susceptibility to develop LBD. We investigated relationships between LBD-specific glucocerebrosidase deficits, GBA-related pathways, and α-synuclein levels in brain tissue from LBD and controls, with and without GBA mutations. We show that LBD is characterised by altered sphingolipid metabolism with prominent elevation of ceramide species, regardless of GBA mutations. Since extracellular vesicles (EV) could be involved in LBD pathogenesis by spreading disease-linked lipids and proteins, we investigated EV derived from post-mortem cerebrospinal fluid (CSF) and brain tissue from GBA mutation carriers and non-carriers. EV purified from LBD CSF and frontal cortex were heavily loaded with ceramides and neurodegeneration-linked proteins including alpha-synuclein and tau. Our in vitro studies demonstrate that LBD EV constitute a “pathological package” capable of inducing aggregation of wild-type alpha-synuclein, mediated through a combination of alpha-synuclein–ceramide interaction and the presence of pathological forms of alpha-synuclein. Together, our findings indicate that abnormalities in ceramide metabolism are a feature of LBD, constituting a promising source of biomarkers, and that GBA mutations likely accelerate the pathological process occurring in sporadic LBD through endolysosomal deficiency.

Highlights

Lewy body disorders (LBD) encompass Parkinson’s disease (PD), Parkinson’s disease dementia (PDD) and dementia with Lewy bodies (DLB), a spectrum of disorders pathologically characterised by neuronal alphasynuclein aggregation [1]
We investigated the effects of heterozygous GBA mutations on the brain lipidome in LBD as we hypothesised that GBA mutations may be associated with the loss of homeostasis in lipid metabolism
Our study clearly indicates the specific accumulation of ceramide species in LBD signifying abnormal sphingolipid metabolism

Summary

Introduction

Lewy body disorders (LBD) encompass Parkinson’s disease (PD), Parkinson’s disease dementia (PDD) and dementia with Lewy bodies (DLB), a spectrum of disorders pathologically characterised by neuronal alphasynuclein aggregation [1]. Accumulating evidence demonstrates that heterozygous mutation of GBA and subsequent reduced GBA enzymatic activity is not sufficient by itself to induce neuronal alpha-synuclein pathology, since there is a significant overlap of GBA activities between GBA mutation carriers and healthy controls [50]. These observations indicate that both the loss of normal function as well as a gain of toxic function by mutant GBA protein might contribute to the risk of alpha-synuclein accumulation in LBD. The underlying mechanism behind the effects of GBA in LBD remains largely unclear; it potentially involves lysosomal dysfunction due to (age-related) alpha-synuclein accumulation and loss of cellular homeostasis due to GBA haploinsufficiency

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