Secretome Analyses Identify FKBP4 as a <i>GBA1</i>-Associated Protein in CSF and iPS Cells from Parkinson’s Disease Patients with <i>GBA1</i> Mutations
Mutations in the <i>GBA1</i> gene increase the risk of developing Parkinson’s disease (PD). However, most carriers of <i>GBA1</i> mutations do not develop PD throughout their lives. The mechanisms of how <i>GBA1</i> mutations contribute to PD pathogenesis remain u...
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MDPI AG
2024-01-01
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| author | Rika Kojima Wojciech Paslawski Guochang Lyu Ernest Arenas Xiaoqun Zhang Per Svenningsson |
| author_facet | Rika Kojima Wojciech Paslawski Guochang Lyu Ernest Arenas Xiaoqun Zhang Per Svenningsson |
| author_sort | Rika Kojima |
| collection | DOAJ |
| description | Mutations in the <i>GBA1</i> gene increase the risk of developing Parkinson’s disease (PD). However, most carriers of <i>GBA1</i> mutations do not develop PD throughout their lives. The mechanisms of how <i>GBA1</i> mutations contribute to PD pathogenesis remain unclear. Cerebrospinal fluid (CSF) is used for detecting pathological conditions of diseases, providing insights into the molecular mechanisms underlying neurodegenerative disorders. In this study, we utilized the proximity extension assay to examine the levels of metabolism-linked protein in the CSF from 17 PD patients carrying <i>GBA1</i> mutations (GBA1-PD) and 17 idiopathic PD (iPD). The analysis of CSF secretome in GBA1-PD identified 11 significantly altered proteins, namely FKBP4, THOP1, GLRX, TXNDC5, GAL, SEMA3F, CRKL, APLP1, LRP11, CD164, and NPTXR. To investigate <i>GBA1</i>-associated CSF changes attributed to specific neuronal subtypes responsible for PD, we analyzed the cell culture supernatant from GBA1-PD-induced pluripotent stem cell (iPSC)-derived midbrain dopaminergic (mDA) neurons. The secretome analysis of GBA1-PD iPSC-derived mDA neurons revealed that five differently regulated proteins overlapped with those identified in the CSF analysis: FKBP4, THOP1, GLRX, GAL, and CRKL. Reduced intracellular level of the top hit, FKPB4, was confirmed via Western Blot. In conclusion, our findings identify significantly altered CSF GBA1-PD-associated proteins with FKPB4 being firmly attributed to mDA neurons. |
| first_indexed | 2024-03-08T15:04:20Z |
| format | Article |
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| issn | 1661-6596 1422-0067 |
| language | English |
| last_indexed | 2024-03-08T15:04:20Z |
| publishDate | 2024-01-01 |
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| series | International Journal of Molecular Sciences |
| spelling | doaj.art-b8dd1357edf74481812500a79f186dcc2024-01-10T15:00:35ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672024-01-0125168310.3390/ijms25010683Secretome Analyses Identify FKBP4 as a <i>GBA1</i>-Associated Protein in CSF and iPS Cells from Parkinson’s Disease Patients with <i>GBA1</i> MutationsRika Kojima0Wojciech Paslawski1Guochang Lyu2Ernest Arenas3Xiaoqun Zhang4Per Svenningsson5Department of Clinical Neuroscience, Karolinska Institutet, 171 76 Stockholm, SwedenDepartment of Clinical Neuroscience, Karolinska Institutet, 171 76 Stockholm, SwedenDepartment of Medical Biochemistry and Biophysics, Karolinska Institutet, 171 77 Stockholm, SwedenDepartment of Medical Biochemistry and Biophysics, Karolinska Institutet, 171 77 Stockholm, SwedenDepartment of Clinical Neuroscience, Karolinska Institutet, 171 76 Stockholm, SwedenDepartment of Clinical Neuroscience, Karolinska Institutet, 171 76 Stockholm, SwedenMutations in the <i>GBA1</i> gene increase the risk of developing Parkinson’s disease (PD). However, most carriers of <i>GBA1</i> mutations do not develop PD throughout their lives. The mechanisms of how <i>GBA1</i> mutations contribute to PD pathogenesis remain unclear. Cerebrospinal fluid (CSF) is used for detecting pathological conditions of diseases, providing insights into the molecular mechanisms underlying neurodegenerative disorders. In this study, we utilized the proximity extension assay to examine the levels of metabolism-linked protein in the CSF from 17 PD patients carrying <i>GBA1</i> mutations (GBA1-PD) and 17 idiopathic PD (iPD). The analysis of CSF secretome in GBA1-PD identified 11 significantly altered proteins, namely FKBP4, THOP1, GLRX, TXNDC5, GAL, SEMA3F, CRKL, APLP1, LRP11, CD164, and NPTXR. To investigate <i>GBA1</i>-associated CSF changes attributed to specific neuronal subtypes responsible for PD, we analyzed the cell culture supernatant from GBA1-PD-induced pluripotent stem cell (iPSC)-derived midbrain dopaminergic (mDA) neurons. The secretome analysis of GBA1-PD iPSC-derived mDA neurons revealed that five differently regulated proteins overlapped with those identified in the CSF analysis: FKBP4, THOP1, GLRX, GAL, and CRKL. Reduced intracellular level of the top hit, FKPB4, was confirmed via Western Blot. In conclusion, our findings identify significantly altered CSF GBA1-PD-associated proteins with FKPB4 being firmly attributed to mDA neurons.https://www.mdpi.com/1422-0067/25/1/683Parkinson’s disease<i>GBA1</i>secretomecerebrospinal fluidhuman-induced pluripotent stem cells (hiPSCs)FKBP4 |
| spellingShingle | Rika Kojima Wojciech Paslawski Guochang Lyu Ernest Arenas Xiaoqun Zhang Per Svenningsson Secretome Analyses Identify FKBP4 as a <i>GBA1</i>-Associated Protein in CSF and iPS Cells from Parkinson’s Disease Patients with <i>GBA1</i> Mutations International Journal of Molecular Sciences Parkinson’s disease <i>GBA1</i> secretome cerebrospinal fluid human-induced pluripotent stem cells (hiPSCs) FKBP4 |
| title | Secretome Analyses Identify FKBP4 as a <i>GBA1</i>-Associated Protein in CSF and iPS Cells from Parkinson’s Disease Patients with <i>GBA1</i> Mutations |
| title_full | Secretome Analyses Identify FKBP4 as a <i>GBA1</i>-Associated Protein in CSF and iPS Cells from Parkinson’s Disease Patients with <i>GBA1</i> Mutations |
| title_fullStr | Secretome Analyses Identify FKBP4 as a <i>GBA1</i>-Associated Protein in CSF and iPS Cells from Parkinson’s Disease Patients with <i>GBA1</i> Mutations |
| title_full_unstemmed | Secretome Analyses Identify FKBP4 as a <i>GBA1</i>-Associated Protein in CSF and iPS Cells from Parkinson’s Disease Patients with <i>GBA1</i> Mutations |
| title_short | Secretome Analyses Identify FKBP4 as a <i>GBA1</i>-Associated Protein in CSF and iPS Cells from Parkinson’s Disease Patients with <i>GBA1</i> Mutations |
| title_sort | secretome analyses identify fkbp4 as a i gba1 i associated protein in csf and ips cells from parkinson s disease patients with i gba1 i mutations |
| topic | Parkinson’s disease <i>GBA1</i> secretome cerebrospinal fluid human-induced pluripotent stem cells (hiPSCs) FKBP4 |
| url | https://www.mdpi.com/1422-0067/25/1/683 |
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