A candidate loss-of-function variant in SGIP1 causes synaptic dysfunction and recessive parkinsonism
Summary: Synaptic dysfunction is recognized as an early step in the pathophysiology of parkinsonism. Several genetic mutations affecting the integrity of synaptic proteins cause or increase the risk of developing disease. We have identified a candidate causative mutation in synaptic “SH3GL2 Interacting Protein 1” (SGIP1), linked to early-onset parkinsonism in a consanguineous Arab family. Additionally, affected siblings display intellectual, cognitive, and behavioral dysfunction. Metabolic network analysis of [18F]-fluorodeoxyglucose positron emission tomography scans shows patterns very similar to those of idiopathic Parkinson’s disease. We show that the identified SGIP1 mutation causes a loss of protein function, and analyses in newly created Drosophila models reveal movement defects, synaptic transmission dysfunction, and neurodegeneration, including dopaminergic synapse loss. Histology and correlative light and electron microscopy reveal the absence of synaptic multivesicular bodies and the accumulation of degradative organelles. This research delineates a putative form of recessive parkinsonism, converging on defective synaptic proteostasis and opening avenues for diagnosis, genetic counseling, and treatment.
Authors
- Patrick Scott (ORCID: https://orcid.org/0000-0002-4917-8171)
- Marianna Decet (ORCID: https://orcid.org/0000-0003-3387-9720)
- Samir Al‐Adawi (ORCID: https://orcid.org/0000-0002-9858-5582)
- Jef Swerts (ORCID: https://orcid.org/0000-0002-3380-6030)
- Douja Meftah
- Eliana Nachman (ORCID: https://orcid.org/0000-0002-2069-6469)
- Patrik Verstreken (ORCID: https://orcid.org/0000-0002-5073-5393)
- David Eidelberg (ORCID: https://orcid.org/0000-0002-0854-864X)
- Sandra F. Gallego (ORCID: https://orcid.org/0000-0001-7960-9860)
- Carles Calatayud (ORCID: https://orcid.org/0000-0003-0032-4198)
- Natalie Kaempf (ORCID: https://orcid.org/0000-0002-5466-3972)
- Sabine Kuenen (ORCID: https://orcid.org/0000-0001-9135-5293)
- Ramachandiran Nandhagopal (ORCID: https://orcid.org/0000-0002-2379-0055)
- Nils Schoovaerts (ORCID: https://orcid.org/0000-0003-0990-6784)
- Roman Praschberger (ORCID: https://orcid.org/0000-0001-7162-2403)
- Abdullah Rashid Al-Asmi (ORCID: https://orcid.org/0000-0002-2851-8157)
- Chris C. Tang
Institutions
- Feinstein Institute for Medical Research (US)
- Centre Hospitalier Universitaire Sainte-Justine (CA)
- Center for Neurosciences (US)
- VIB-KU Leuven Center for Brain & Disease Research (BE)
- Sultan Qaboos University (OM)
Publication Details
- Journal
- Cell Reports Medicine
- Published
- 2024-09-26
- DOI
- https://doi.org/10.1016/j.xcrm.2024.101749
- Citations
- 5
- Primary Topic
- Neuroscience and Neuropharmacology Research
- Type
- article
- Field-Weighted Citation Impact
- 1.34
Funders
- Fonds Wetenschappelijk Onderzoek
- KU Leuven
- Vlaamse regering
- National Institutes of Health
- H2020 European Research Council