GBA Mutations Influence the Release and Pathological Effects of Small Extracellular Vesicles from Fibroblasts of Patients with Parkinson’s Disease

Cerri, Silvia; Ghezzi, Cristina; Ongari, Gerardo; Croce, Stefania; Avenali, Micol; Zangaglia, Roberta; Monte, Donato A. Di; Valente, Enza Maria; Blandini, Fabio

doi:10.3390/ijms22042215

Cited by 23 publications

(12 citation statements)

References 44 publications

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“…In homozygous and heterozygous form, E326K mutations are not associated with a significant loss of GCase expression or activity in fibroblasts and SH-SY5Y cells. These findings are supported by previous literature demonstrating the E326K variant generally reduces GCase activity to a lesser extent than other pathogenic GBA mutations (16,(56)(57)(58)(59)(60)(61), while L444P and N370S variants are reported to induce a loss of GCase function (30,31,42,(61)(62)(63)(64)(65)(66)(67), as demonstrated in this study.…”

Section: Discussionsupporting

confidence: 93%

TheGBAvariant E326K is associated with alpha-synuclein aggregation and lipid droplet accumulation in human cell lines

Smith

Bolsinger

Chau

et al. 2022

Preprint

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Sequence variants or mutations in the GBA gene are numerically the most important risk factor for Parkinson disease (PD). The GBA gene encodes for the lysosomal hydrolase enzyme, glucocerebrosidase (GCase). GBA mutations often reduce GCase activity and lead to impairment of the autophagy-lysosomal pathway, which is important in the turnover of alpha-synuclein, accumulation of which is a key pathological hallmark of PD. Although the E326K variant is one of the most common GBA variants associated with PD, there is limited understanding of its biochemical effects. We have characterised homozygous and heterozygous E326K variants in human fibroblasts. We found that E326K variants did not cause significant loss of GCase protein or activity, endoplasmic reticulum (ER) retention or ER stress, in contrast to the L444P GBA mutation. This was confirmed in human dopaminergic SH-SY5Y neuroblastoma cell lines over-expressing GCase with either E326K or L444P protein. Despite no loss of GCase activity, a significant increase of insoluble alpha-synuclein aggregates in E326K and L444P mutants was observed. Notably, SH-SY5Y over-expressing E326K demonstrated a significant increase in lipid droplet number under basal conditions, which was exacerbated following treatment with the fatty acid oleic acid. Similarly, a significant increase in lipid droplet formation following lipid loading was observed in heterozygous and homozygous E326K fibroblasts. In conclusion, the work presented here demonstrates that the E326K mutation behaves differently to common loss of function GBA mutations, however lipid dyshomeostasis and alpha-synuclein pathology is still evident.

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Section: Discussionsupporting

confidence: 93%

TheGBAvariant E326K is associated with alpha-synuclein aggregation and lipid droplet accumulation in human cell lines

Smith

Bolsinger

Chau

et al. 2022

Preprint

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“…The plasma exosomal/total α-syn ratio is associated with GCase activity, and it correlates with severity (motor deficiency) in PD patients ( Cerri et al, 2018 ; Johnson et al, 2020 ), proposing the link between lysosomal dysfunction with increased exosome secretion. Similar results were reported in fibroblasts derived from PD patients with or without GBA1 , in which defective GCase activity increased the release of exosomes ( Cerri et al, 2021 ). Isolated exosomes from these cells caused increased levels of phospho-α-syn in SH-SY5Y recipient cells, overexpressing wild-type α-syn ( Cerri et al, 2021 ).…”

Section: Impact Of Autophagy-lysosomal Pathway In Parkinson’s Disease...supporting

confidence: 84%

“…Similar results were reported in fibroblasts derived from PD patients with or without GBA1 , in which defective GCase activity increased the release of exosomes ( Cerri et al, 2021 ). Isolated exosomes from these cells caused increased levels of phospho-α-syn in SH-SY5Y recipient cells, overexpressing wild-type α-syn ( Cerri et al, 2021 ). Interesting, this effect was not due to a seeding effect since fibroblasts are α-syn-free.…”

Section: Impact Of Autophagy-lysosomal Pathway In Parkinson’s Disease...supporting

confidence: 84%

Contribution of Autophagy-Lysosomal Pathway in the Exosomal Secretion of Alpha-Synuclein and Its Impact in the Progression of Parkinson’s Disease

Sepúlveda

Cisternas-Olmedo

Arcos

et al. 2022

Front. Mol. Neurosci.

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Parkinson’s disease (PD) is caused by the degeneration of dopaminergic neurons due to an accumulation of intraneuronal abnormal alpha-synuclein (α-syn) protein aggregates. It has been reported that the levels of exosomal α-syn of neuronal origin in plasma correlate significantly with motor dysfunction, highlighting the exosomes containing α-syn as a potential biomarker of PD. In addition, it has been found that the selective autophagy-lysosomal pathway (ALP) contributes to the secretion of misfolded proteins involved in neurodegenerative diseases. In this review, we describe the evidence that supports the relationship between the ALP and α-syn exosomal secretion on the PD progression and its implications in the diagnosis and progression of this pathology.

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“…The expression of α-Syn in the skin has been mainly ascribed to peripheral nerve terminals and melanocytes (Rodriguez-Leyva et al, 2016; Kim et al, 2019). Dermal fibroblasts are also another possible source of α-Syn accumulation in the aged skin, releasing exosomes containing α-Syn and pro-inflammatory mediators by cell-to-cell transmission from the dermis to the epidermis (Danzer et al, 2012; Cerri et al, 2021). However, one study also showed α-Syn immunopositive keratinocytes from the skin of patients with Parkinson’s disease and atypical parkinsonism (Rodríguez-Leyva et al, 2014).…”

Section: Discussionmentioning

confidence: 99%

Oligomeric α-Synuclein induces skin degeneration in a reconstructed human epidermis model

Oliveira

Vecchi²,

Dakic³

et al. 2021

Preprint

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Cell senescence may promote epidermal inflammation and degeneration, termed as inflammaging, which is accompanied by keratinocyte loss, resulting in fine lines of wrinkles. Recent findings showed that healthy elderly skin expresses age- and neuron-related amyloidogenic proteins, such as tau, β-Amyloid34, and α-synuclein (α-Syn), typically found in patients with neurodegenerative diseases. These proteins form toxic aggregates that trigger inflammatory signals. Herein, we investigated the impact of oligomeric α-Syn (Oα-Syn) on the neurosphere (NP) and the reconstructed human epidermis (RHE) 3D models. First, we found the expression of α-Syn, β-Amyloid, and amyloid precursor protein (APP) in the RHE. Second, we challenged the RHE and NP with Oα-Syn, which decreased RHE regeneration, measured by the percentage of cell proliferation and thickness of the stratum basale, but did not affect NP neurite outgrowth. Oα-Syn did not decrease the number of human neonatal epidermal keratinocytes (HEKn) but, as seen for the RHE, it also decreased the proliferation of HEKn. We confirmed that the oligomeric, and not the monomeric α-Syn species, accounted for the proliferation-decreasing effect. Oα-Syn also increased the NF-κB nuclear translocation in HEKn analyzed by nucleus/cytoplasm NF-κB fluorescence intensity. In addition, Oα-Syn triggered inflammation in the RHE, by increasing the mRNA levels of IL-1β and tumor necrosis factor-alpha (TNF-α), and the release of TNF-α in a time-dependent manner. These findings show that Oα-Syn does not affect neurite outgrowth but induces a decrease in keratinocyte proliferation along with epidermal inflammation. With our tridimensional models, we demonstrated that the neurodegenerative protein Oα-Syn also degenerates the epidermis, drawing attention to the need of target-based screening to prevent and treat the effects of skin aging.

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GBA Mutations Influence the Release and Pathological Effects of Small Extracellular Vesicles from Fibroblasts of Patients with Parkinson’s Disease

Cited by 23 publications

References 44 publications

TheGBAvariant E326K is associated with alpha-synuclein aggregation and lipid droplet accumulation in human cell lines

TheGBAvariant E326K is associated with alpha-synuclein aggregation and lipid droplet accumulation in human cell lines

Contribution of Autophagy-Lysosomal Pathway in the Exosomal Secretion of Alpha-Synuclein and Its Impact in the Progression of Parkinson’s Disease

Oligomeric α-Synuclein induces skin degeneration in a reconstructed human epidermis model

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