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Disruption of lysosomal proteolysis in astrocytes facilitates midbrain organoid proteostasis failure in an early-onset Parkinson's disease model.

ABSTRACT: Supporting data for "Disruption of lysosomal proteolysis in astrocytes facilitates midbrain proteostasis failure in an early-onset PD model", DOI: T.B.D. Related to Figure 4A and S4A-B. KN43-66 - TMTpro | 4plex | Whole cell proteome - MS3 KN67-72 - TMTpro | 4plex | Enriched Phospho-peptides - MS2 KN73-96 - TMT | 9plex | Whole cell proteome - MS2

INSTRUMENT(S): Orbitrap Eclipse

ORGANISM(S): Homo Sapiens (ncbitaxon:9606)

SUBMITTER: Alban Ordureau

PROVIDER: MSV000090202 | MassIVE | Wed Aug 24 14:45:00 BST 2022

REPOSITORIES: MassIVE

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Disruption of lysosomal proteolysis in astrocytes facilitates midbrain organoid proteostasis failure in an early-onset Parkinson's disease model.

Morrone Parfitt Gustavo G Coccia Elena E Goldman Camille C Whitney Kristen K Reyes Ricardo R Sarrafha Lily L Nam Ki Hong KH Sohail Soha S Jones Drew R DR Crary John F JF Ordureau Alban A Blanchard Joel J Ahfeldt Tim T

Nature communications 20240110 1

Accumulation of advanced glycation end products (AGEs) on biopolymers accompanies cellular aging and drives poorly understood disease processes. Here, we studied how AGEs contribute to development of early onset Parkinson's Disease (PD) caused by loss-of-function of DJ1, a protein deglycase. In induced pluripotent stem cell (iPSC)-derived midbrain organoid models deficient for DJ1 activity, we find that lysosomal proteolysis is impaired, causing AGEs to accumulate, α-synuclein (α-syn) phosphoryl ...[more]

PMID: 38200091

Similar Datasets

Disruption of lysosomal proteolysis in astrocytes facilitates midbrain organoid proteostasis failure in an early-onset Parkinson's disease model.

Project description:Accumulation of advanced glycation end products (AGEs) on biopolymers accompanies cellular aging and drives poorly understood disease processes. Here, we studied how AGEs contribute to development of early onset Parkinson's Disease (PD) caused by loss-of-function of DJ1, a protein deglycase. In induced pluripotent stem cell (iPSC)-derived midbrain organoid models deficient for DJ1 activity, we find that lysosomal proteolysis is impaired, causing AGEs to accumulate, α-synuclein (α-syn) phosphorylation to increase, and proteins to aggregate. We demonstrated these processes are at least partly driven by astrocytes, as DJ1 loss reduces their capacity to provide metabolic support and triggers acquisition of a pro-inflammatory phenotype. Consistently, in co-cultures, we find that DJ1-expressing astrocytes are able to reverse the proteolysis deficits of DJ1 knockout midbrain neurons. In conclusion, astrocytes' capacity to clear toxic damaged proteins is critical to preserve neuronal function and their dysfunction contributes to the neurodegeneration observed in a DJ1 loss-of-function PD model.

| S-EPMC10781970 | biostudies-literature

RNA-seq of human midbrain organoid models of Parkinson's Disease

Project description:Parkinson’s disease (PD) is a prevalent neurodegenerative disorder that is characterized by the selective loss of midbrain dopamine (DA)-producing neurons and the formation of α-synuclein (α-syn)-containing inclusions named Lewy bodies (LBs). Here, we report that the loss of glucocerebrosidase (GCase), coupled with α-syn overexpression, result in substantial accumulation of detergent-resistant α-syn aggregates and Lewy body-like inclusions (LBLIs) in human midbrain-like organoids (hMLOs). These LBLIs exhibit a highly similar structure to PD-associated LBs, by displaying a spherically symmetric morphology with an eosinophilic core, and containing α-syn and ubiquitin. Importantly, hMLOs generated from PD patient-derived inducible pluripotent stem cells (iPSCs) harboring SNCA triplication also exhibit subsequent degeneration of DA neurons and LBLI formation upon chronic GCase inhibitor treatment. Taken together, our hMLOs harbouring two major PD risk factors (GCase deficiency and overproduced α-syn) successfully recapitulate major pathophysiological signatures of the disease, and highlight the broad utility of brain organoid technology in modeling human neurodegenerative diseases.

2021-08-13 | E-MTAB-7302 | biostudies-arrayexpress

RNA-seq of human midbrain organoid models of Parkinson's Disease

Project description:RNA-seq of human midbrain organoid models of Parkinson's Disease

| PRJEB45026 | ENA

TMTPro Complementary Ion Quantification Increase Plexing and Sensitivity for Accurate Multiplexed Proteomics at the MS2 level

Project description:The ability of the TMTPro isobaric labeling reagents to form complementary ions for accurate multiplexed proteomics at the MS2 level was investigated. Human and yeast peptides were labeled in distinct ratios to analyze the effect of interference on the quantification accuracy. A method, TMTProC, was developed and optimized for accurate, sensitive MS2-level quantification of up to 8 conditions in one MS-run.

2021-05-11 | PXD021661 | Pride

RNA-seq of cultured cells derived from Parkinson's disease patients [PolyA RNA-seq]

Project description:High throughput sequencing of poly-A RNA from control- and sporadic Parkinson´s disease patient derived fibroblasts (n=15), induced pluripotent stem cells (n=31) and differentiated midbrain neurons (n=15). Fibroblasts and iPSCs do not show major differences on single gene level. In contrast, midbrain neurons derived from Parkinson´s disease patients show changes known to be associated with neurodegenerative diseases.

2018-10-08 | GSE110717 | GEO

Metabolic alterations in Parkinson's disease astrocytes.

Project description:In Parkinson`s disease (PD), the loss of dopaminergic (DA) neurons in the substantia nigra pars compacta is associated with Lewy bodies arising from the accumulation of alpha-synuclein protein which leads ultimately to movement impairment. While PD has been considered a disease of the DA neurons, a glial contribution, in particular that of astrocytes, in PD pathogenesis is starting to be uncovered. Here, we report findings from astrocytes derived from induced pluripotent stem cells of LRRK2 G2019S mutant patients, with one patient also carrying a GBA N370S mutation, as well as healthy individuals. The PD patient astrocytes manifest the hallmarks of the disease pathology including increased expression of alpha-synuclein. This has detrimental consequences, resulting in altered metabolism, disturbed Ca2+ homeostasis and increased release of cytokines upon inflammatory stimulation. Furthermore, PD astroglial cells manifest increased levels of polyamines and polyamine precursors while lysophosphatidylethanolamine levels are decreased, both of these changes have been reported also in PD brain. Collectively, these data reveal an important role for astrocytes in PD pathology and highlight the potential of iPSC-derived cells in disease modeling and drug discovery.

| S-EPMC7468111 | biostudies-literature

The Parkinson's disease associated mutation LRRK2-G2019S affects astrocyte specification

Project description:We report the altered transcriptomic profile of astrocytes in midbrain organoids differentiated for 35 and 70 days and generated from a stem cell line carrying the LRRK2-G2019S mutation compared to the isogenic pair.

2020-05-01 | GSE133894 | GEO

Transcriptome analysis of human immortilized astrocytes reprogrammed into dopaminergic neurons

Project description:We directly reprogram human astrocytes (hIA) in vitro into induced dopaminergic neurons (iDAs). This process requires three transcription factors, NEUROD1, ASCL1 and LMX1A as well as one microRNA, mir218. This combined protocol gives rise to human astrocyte-derived iDAs with appropriate midbrain markers as defined by analyzing markers derived from human embryonic ventral midbrain samples at 7 and 9 weeks of age.

2017-03-27 | GSE93528 | GEO

scRNA-seq of Human midbrain organoids differentiated from WTSIi018-B-1 (healthy) and EDi001-B (Parkinson's Disease) iPSCs

Project description:Day 49 organoid differentiation of midbrain organoids

2023-01-01 | E-MTAB-12339 | biostudies-arrayexpress

An iPSC Model of Early Onset Parkinson's Disease

Project description:Early onset Parkinson’s Disease (onset <50 years) accounts for between 10-20 percent of all patients. While some of these cases are associated with specific mutations, the majority are sporadic where the cause is unknown. We generated induced pluripotent stem cells from sporadic early onset patients and differentiated them to dopamine neurons. At early stages in culture (30 days) we found significant elevations in soluble α-synuclein protein levels when compared to controls. This was associated with reductions in lysosomal membrane proteins such as LAMP1 and an increase in phosphorylated protein kinase C-α (p-PKCα). Testing activators of lysosomal function showed that specific phorbal esters reduced both α-synuclein and p-PKCα levels and increased LAMP1 expression. Interestingly, very low doses of the drug PEP005 were able to reduce α-synuclein levels without affecting p-PKCα. Similar effects of PEP005 on α-synuclein expression were seen following infusion into the mouse brain. Our data show that early onset sporadic Parkinson’s Disease can be accurately predicted using a ratio of α-synuclein and p-PKCα in dopamine neural cultures derived from patient iPSC’s and that specific phorbal esters can alter both biomarkers making these drugs promising candidates to treat Parkinson’s Disease.

2019-12-06 | PXD011326 | Pride

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