Post-translational proteomics platform identifies neurite outgrowth impairments in Parkinson’s disease GBA-N370S dopamine neurons

Bogetofte, Helle; Ryan, Brent J.; Jensen, Pia; Schmidt, Sissel Ida; Vergoossen, Dana L.E.; Barnkob, Mike Bogetofte; L, Kiani; Chughtai, Uroosa; Héon-Roberts, Rachel; Caiazza, Maria Claudia; McGuinness, William; Márquez-Gómez, Ricardo; Vowles, Jane; Bunn, Fiona S.; Brandes, Janine; Kilfeather, Peter; Connor, Jack P.; Fernandes, Hugo J. R.; Caffrey, Tara M.; Meyer, Morten; Cowley, Sally A.; Larsen, Martin R.; Wade‐Martins, Richard

doi:10.1016/j.celrep.2023.112180

Cited by 15 publications

(13 citation statements)

References 87 publications

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“…The brain ECM has been shown to closely affect neurite outgrowth and connectivity during neural development 75 . In alignment with our observed dysregulation of ECM-related pathways and the connection to neurite outgrowth, Bogetofte et al recently demonstrated neurite outgrowth impairments in proteomic analysis of N370S GBA1 mutant DA neurons 76 . The synaptic deficits that are also a shared phenotype in PD suggest a temporal correlation between the synaptic impairment and the ECM deficits that needs further investigation in the context of PD.…”

Section: Discussionsupporting

confidence: 91%

Synaptic dysfunction and extracellular matrix dysregulation in dopaminergic neurons from sporadic and E326K-GBA1 Parkinson’s disease patients

Rosh,

Tripathi,

Hussein

et al. 2024

npj Parkinsons Dis.

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Parkinson’s disease (PD) is a neurodegenerative disease with both genetic and sporadic origins. In this study, we investigated the electrophysiological properties, synaptic activity, and gene expression differences in dopaminergic (DA) neurons derived from induced pluripotent stem cells (iPSCs) of healthy controls, sporadic PD (sPD) patients, and PD patients with E326K-GBA1 mutations. Our results demonstrate reduced sodium currents and synaptic activity in DA neurons derived from PD patients with E326K-GBA1 mutations, suggesting a potential contribution to PD pathophysiology. We also observed distinct electrophysiological alterations in sPD DA neurons, which included a decrease in synaptic currents. RNA sequencing analysis revealed unique dysregulated pathways in sPD neurons and E326K-GBA1 neurons, further supporting the notion that molecular mechanisms driving PD may differ between PD patients. In agreement with our previous reports, Extracellular matrix and Focal adhesion pathways were among the top dysregulated pathways in DA neurons from sPD patients and from patients with E326K-GBA1 mutations. Overall, our study further confirms that impaired synaptic activity is a convergent functional phenotype in DA neurons derived from PD patients across multiple genetic mutations as well as sPD. At the transcriptome level, we find that the brain extracellular matrix is highly involved in PD pathology across multiple PD-associated mutations as well as sPD.

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Section: Discussionsupporting

confidence: 91%

Synaptic dysfunction and extracellular matrix dysregulation in dopaminergic neurons from sporadic and E326K-GBA1 Parkinson’s disease patients

Rosh,

Tripathi,

Hussein

et al. 2024

npj Parkinsons Dis.

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“…Interestingly, glycoproteome analysis revealed a number of significantly enriched pathways, including ceramide catabolic processes, and also an increased level of glycosylated LAMP1, LAMP2 and cathepsin D, which are necessary for transport from the ER via the Golgi to the lysosome, in GBA-PD iPSC-dopamine neurons. Increased phosphorylated mTOR level was supported with Western blot analysis [66]. Earlier, we found differences in lysosomal hydrolase activity (alpha-galactosidase (GLA), alpha-iduronidase (IDUA)) in iPCS neurons of GBA-PD compared to GBA carriers, suggesting that a more pronounced imbalance of sphingolipid metabolism may lead to impaired lysosomal clearance and launch the diseases associated with GCase deficiency [67].…”

Section: Discussionmentioning

confidence: 57%

“…We found a similar alteration in the PI3K-Akt-mTOR pathway in condition of GCase dysfunction in our PD models, both in primary macrophages from patients with GBA-PD and in the double toxic model MPTP+CBE-treated mice (Figure 6B). Recently, disturbances in the autophagy-lysosomal pathway, which co-occur with upstream perturbations in mTOR activation, were found using proteome analysis of induced pluripotent stem cell (iPSC) dopamine neurons of GBA-PD patients [66]. Additionally, single-cell RNA sequencing and proteomics of brain samples from GBA-PD patients confirmed reduced CMA activity and proteome changes comparable to those found in brain samples from heterozygous L444P/N GBA1 mice [49].…”

Section: Discussionmentioning

confidence: 88%

Whole Transcriptome Analysis of Substantia Nigra in Mice with MPTP-Induced Parkinsonism Bearing Defective Glucocerebrosidase Activity

Usenko

Bezrukova

Rudenok

et al. 2023

IJMS

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Mutations in the GBA1 gene represent the major genetic risk factor for Parkinson’s disease (PD). The lysosomal enzyme beta-glucocerebrosidase (GCase) encoded by the GBA1 gene participates in both the endolysosomal pathway and the immune response. Disruption of these mechanisms is involved in PD pathogenesis. However, molecular mechanisms of PD associated with GBA1 mutations (GBA-PD) are unknown today in particular due to the partial penetrance of GBA1 variants in PD. The modifiers of GBA1 penetrance have not been elucidated. We characterized the transcriptomic profiles of cells from the substantia nigra (SN) of mice with co-injection with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and selective inhibitor of GCase activity (conduritol-β-epoxide, (CBE)) to mimic PD bearing GCase dysfunction (MPTP+CBE), mice treated with MPTP, mice treated with CBE and control mice treated with injection of sodium chloride (NaCl) (vehicle). Differential expression analysis, pathway enrichment analysis, and outlier detection were performed. Functional clustering of differentially represented transcripts revealed more processes associated with the functioning of neurogenesis, inflammation, apoptosis and autophagy in MPTP+CBE and MPTP mice than in vehicle mice, with a more pronounced alteration of autophagy processes in MPTP+CBE mice than in MPTP mice. The PI3K-Akt-mTOR signaling pathway may be considered a potential target for therapy in PD with GCase dysfunction.

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“…variants to senescence and age-related dementias. Impaired neuritogenesis, for instance, was reported for instance in an iPSC-derived neuronal model of Parkinson's disease 49 , cognitive inflexibility was observed in individuals with Parkinson's and Alzheimer's diseases 37 , and imbalance in E/I ratio was similarly noticed in individuals with Alzheimer's disease 50 .…”

Section: In Vitro Functional Investigations On T Cells Withmentioning

confidence: 99%

Unveiling the crucial neuronal role of the proteasomal ATPase subunit genePSMC5in neurodevelopmental proteasomopathies

Küry,

Stanton,

van Woerden

et al. 2024

Preprint

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Neurodevelopmental proteasomopathies have recently emerged as a distinct class of neurodevelopmental disorders (NDD). These conditions involve alterations in genes of the 26S proteasome, a protein complex essential for maintaining protein homeostasis in eukaryotic cells. Our study identified 23 unique variants in PSMC5, which encodes the AAA-ATPase proteasome subunit PSMC5/Rpt6, causing syndromic NDD in 38 unrelated individuals. PSMC5 loss-of-function resulted in abnormal protein aggregation, profoundly affecting innate immune signaling, mitophagy rate, and lipid metabolism in samples of affected individuals samples. Moreover, the morphology of human hippocampal neurons was altered by overexpression of PSMC5 variants, while PSMC5 knockdown led to impaired reversal learning in flies and loss of excitatory synapses in rat hippocampal neurons. Promisingly, targeting key integrated stress response components like PKR and GCN2 kinases alleviated immune alterations in cells of affected individuals. These findings deepen our understanding of the molecular mechanisms underlying neurodevelopmental proteasomopathies and link these disorders with neurodegenerative disease research.

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Post-translational proteomics platform identifies neurite outgrowth impairments in Parkinson’s disease GBA-N370S dopamine neurons

Cited by 15 publications

References 87 publications

Synaptic dysfunction and extracellular matrix dysregulation in dopaminergic neurons from sporadic and E326K-GBA1 Parkinson’s disease patients

Synaptic dysfunction and extracellular matrix dysregulation in dopaminergic neurons from sporadic and E326K-GBA1 Parkinson’s disease patients

Whole Transcriptome Analysis of Substantia Nigra in Mice with MPTP-Induced Parkinsonism Bearing Defective Glucocerebrosidase Activity

Unveiling the crucial neuronal role of the proteasomal ATPase subunit genePSMC5in neurodevelopmental proteasomopathies

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