Affinage

SYNJ1

Synaptojanin-1 · UniProt O43426

Length
1573 aa
Mass
173.1 kDa
Annotated
2026-06-10
31 papers in source corpus 11 papers cited in narrative 11 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 5/5 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

SYNJ1 encodes synaptojanin 1, a dual-domain phosphoinositide phosphatase whose Sac1-like and 5-phosphatase activities govern phosphoinositide turnover required for membrane trafficking and synaptic function (PMID:23804563, PMID:23804577, PMID:27435091). Genotype–phenotype dissection establishes two distinct disease mechanisms: a selective Sac1-domain mutation (R258Q) that abolishes activity against Sac1-domain substrates causes early-onset parkinsonism (PMID:23804563, PMID:23804577), whereas variants that impair or eliminate both phosphatase activities cause severe neonatal epileptic encephalopathy (PMID:27435091). Beyond the synapse, loss of Synj1 disrupts early endosomal homeostasis, enlarging early endosomes and impairing transferrin recycling without affecting EGF receptor trafficking, defects reversible by re-expression (PMID:29515184); conversely, Synj1 overexpression is sufficient to recapitulate these endosomal trafficking abnormalities (PMID:35646085). In R258Q (PARK20) patient cells, compromised ER exit and ER-to-Golgi trafficking trigger ER stress through the PERK/eIF2α/ATF4/CHOP UPR pathway and elevate oxidative stress, both relieved by PERK inhibition (PMID:31316342). Synj1 also sustains synaptic vesicle recycling at sensory hair-cell ribbon synapses (PMID:33584199) and functionally interacts with the phosphoinositide-handling machinery of DNAJC6/Auxilin to preserve neuronal integrity (PMID:36739293).

Mechanistic history

Synthesis pass · year-by-year structured walk · 9 steps
  1. 2013 High

    Establishing that the Sac1-like domain is enzymatically active and that its selective inactivation underlies parkinsonism connected a specific catalytic defect to disease.

    Evidence In vitro phosphatase assay of the R258Q mutant, independently replicated by two labs

    PMID:23804563 PMID:23804577

    Open questions at the time
    • Does not define in vivo Sac1-domain substrates at the synapse
    • Does not explain how selective Sac1 loss produces a parkinsonian phenotype mechanistically
  2. 2016 High

    Distinguishing partial dual-phosphatase impairment from near-complete loss separated the molecular basis of neonatal epileptic encephalopathy from parkinsonism, defining a dose/activity-dependent phenotypic spectrum.

    Evidence In vitro dual phosphatase assay with mutagenesis plus RT-qPCR mRNA quantification and patient sequencing

    PMID:27435091

    Open questions at the time
    • Does not establish neuronal circuits affected by complete loss
    • Does not resolve why 5-phosphatase versus Sac1 loss produces divergent neurological outcomes
  3. 2018 High

    Demonstrating endosomal enlargement and selective transferrin recycling defects rescued by re-expression extended Synj1 function beyond the synaptic vesicle cycle to general early endosomal homeostasis.

    Evidence siRNA knockdown with rescue, endosomal imaging, transferrin recycling assay, and patient fibroblast validation

    PMID:29515184

    Open questions at the time
    • Does not identify which phosphoinositide pool at endosomes is dysregulated
    • Does not explain cargo selectivity sparing EGFR
  4. 2019 Medium

    Linking R258Q to impaired ER exit and PERK/UPR-driven ER and oxidative stress provided a downstream cellular pathology connecting Synj1 loss to neurodegeneration-relevant stress responses.

    Evidence ER/Golgi morphology and UPR marker analysis with PERK inhibitor rescue of ROS in PARK20 fibroblasts

    PMID:31316342

    Open questions at the time
    • Does not establish whether the ER trafficking defect is a direct phosphoinositide consequence
    • Single lab, patient-fibroblast model only
  5. 2021 Medium

    Showing diminished phase-locking and recovery of vesicle release at hair-cell ribbon synapses defined a specialized role for Synj1 in sustaining high-rate synaptic vesicle recycling.

    Evidence Zebrafish synj1 mutant electrophysiology and behavioral postural assays

    PMID:33584199

    Open questions at the time
    • Does not connect ribbon synapse defects to specific phosphoinositide substrates
    • Mammalian relevance not tested
  6. 2022 Medium

    Demonstrating that Synj1 overexpression alone recapitulates endosomal trafficking defects established that dosage in both directions disturbs endosomal homeostasis, relevant to gene-dose conditions.

    Evidence Synj1 overexpression in fetal fibroblasts with endosomal imaging and transferrin recycling compared to Down syndrome cells

    PMID:35646085

    Open questions at the time
    • Does not establish causal contribution within intact Down syndrome genetic context
    • Mechanism linking excess phosphatase activity to endosome enlargement unresolved
  7. 2023 Medium

    Genetic epistasis with DNAJC6/Auxilin showed Synj1 phosphoinositide metabolism acts in a common pathway maintaining neuronal integrity.

    Evidence Drosophila Synj1 overexpression rescue of DNAJC6 mutant lipid, synaptic, and neurodegeneration phenotypes with lipidomics

    PMID:36739293

    Open questions at the time
    • Does not define direct biochemical coupling between Synj1 and Auxilin
    • Human relevance inferred from Drosophila
  8. 2023 Low

    Low-confidence findings began mapping additional partners and functions, implicating Synj1 in dopamine handling and physical association with TSP-1.

    Evidence siRNA in PC12 cells with dopamine measurement; Co-IP and knockdown in brain/SH-SY5Y cells

    PMID:37419331 PMID:37667188

    Open questions at the time
    • Single-method dopamine assay without mechanistic pathway placement
    • TSP-1 interaction lacks reciprocal pulldown validation
  9. 2025 Low

    Proximity proteomics positioned Synj1 within the BIN1-associated presynaptic vesicle cycle network.

    Evidence BIN1 TurboID proximity labeling in mouse brain neurons with PLA validation (preprint)

    Open questions at the time
    • Proximity does not establish direct interaction
    • Preprint, single lab

Open questions

Synthesis pass · forward-looking unresolved questions
  • How the two catalytic domains differentially shape phosphoinositide pools across synaptic, endosomal, and ER compartments to produce distinct disease phenotypes remains unresolved.
  • No experimentally validated structure of full-length Synj1
  • In vivo substrate pools per domain undefined
  • Mechanism connecting trafficking defects to neurodegeneration not established

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0008289 lipid binding 3 GO:0016787 hydrolase activity 2
Localization
GO:0005768 endosome 2 GO:0005886 plasma membrane 1
Pathway
R-HSA-5653656 Vesicle-mediated transport 2 R-HSA-112316 Neuronal System 1 R-HSA-8953897 Cellular responses to stimuli 1
Partners
BIN1DNAJC6TSP1

Evidence

Reading pass · 11 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2013 The R258Q mutation in the Sac1-like inositol phosphatase domain of SYNJ1 impairs the phosphatase activity of SYNJ1 against its Sac1 domain substrates in vitro, establishing that this domain has enzymatic activity toward phosphoinositide substrates. In vitro phosphatase activity assay with mutant (p.Arg258Gln) SYNJ1 Human mutation High 23804563 23804577
2016 A missense variant (p.Tyr888Cys) in SYNJ1 impairs but does not abolish the dual phosphatase activity of SYNJ1 (both Sac1 and 5-phosphatase domains), while premature stop variants almost completely abolish mRNA transcript production, establishing that complete loss of dual phosphatase activity causes severe neonatal epilepsy distinct from the selective Sac1-loss parkinsonism phenotype. In vitro dual phosphatase activity assay; mRNA quantification by RT-qPCR; patient exome/genome sequencing with phenotype correlation Brain : a journal of neurology High 27435091
2018 Depletion of Synj1 causes enlargement and increased number of early endosomes, impairs recycling of transferrin (but does not alter EGF receptor trafficking), and ectopic re-expression of Synj1 rescues these defects, establishing a role for Synj1 in early endosomal homeostasis and recycling trafficking. siRNA knockdown and rescue (ectopic expression) in non-neuronal and neuronal cells; live-cell and fixed imaging of endosomal compartments; transferrin recycling assay; patient-derived fibroblast validation Cell death & disease High 29515184
2019 In PARK20 (SYNJ1 p.Arg258Gln) patient fibroblasts, the ER exit machinery and ER-to-Golgi trafficking are compromised, leading to ER cargo accumulation and induction of ER stress via the PERK/eIF2α/ATF4/CHOP UPR pathway; pharmacological inhibition of PERK (GSK2606414) restores ROS levels, establishing a direct link between Synj1 loss, ER stress, and oxidative stress. Imaging and biochemical analysis of ER/Golgi morphology; UPR marker quantification; PERK inhibitor treatment with ROS measurement in PARK20 patient fibroblasts Frontiers in neuroscience Medium 31316342
2021 Loss of synj1 function in zebrafish disrupts ribbon synapse activity in sensory hair cells: after prolonged mechanical stimulation, phase-locking of afferent nerve activity and recovery of spontaneous synaptic vesicle release are diminished, establishing a specific role for Synj1 in sustaining sustained synaptic vesicle recycling at ribbon synapses. Zebrafish synj1 mutant analysis; vestibulospinal reflex assay; afferent nerve electrophysiology; behavioral postural control assay Frontiers in molecular neuroscience Medium 33584199
2023 In a Drosophila DNAJC6/Auxilin knock-in model, overexpression of Synaptojanin-1 rescues phosphoinositide lipid species alterations, synaptic dysfunction, neurological defects, and neurodegeneration caused by the DNAJC6 mutation, establishing a functional relationship between Synj1-mediated phosphoinositide metabolism and DNAJC6/Auxilin in maintaining neuronal integrity. Drosophila genetic overexpression rescue; lipidomics; neurological behavioral assays; neurodegeneration quantification NPJ Parkinson's disease Medium 36739293
2022 Overexpression of Synj1 in Down syndrome (DS) fetal fibroblasts recapitulates the early endosome enlargement and recycling trafficking defects observed in DS cells, suggesting that elevated Synj1 activity is sufficient to disturb early endosomal homeostasis. Synj1 overexpression in fetal fibroblasts; imaging of endosomal compartments; transferrin recycling assay; comparison to DS patient-derived fibroblasts Frontiers in genetics Medium 35646085
2023 Knockdown of synaptojanin 1 in PC12 cells reduces total and released dopamine, and SYNJ1 protein levels correlate positively with dopamine synthesis and secretion; this establishes a functional role for SYNJ1 in dopamine production and release. siRNA knockdown of SYNJ1 in PC12 cells; measurement of total and released dopamine; Western blot for protein levels BMC genomics Low 37667188
2023 Co-immunoprecipitation verified a physical interaction between SYNJ1 and TSP-1 (thrombospondin-1) proteins in mouse brain, with this interaction attenuated in aged hSNCA*A53T-Tg PD mice; SYNJ1 knockdown in SH-SY5Y cells reduced TSP-1 expression. Co-immunoprecipitation; transcriptomic sequencing after SYNJ1 knockdown; in silico protein-protein docking Behavioural brain research Low 37419331
2025 BIN1 isoform 1 proximity labeling (TurboID) in mouse brain neurons identified SYNJ1 as a proximal/interacting partner of BIN1, placing SYNJ1 in the synaptic vesicle cycle network associated with BIN1 at presynaptic terminals. TurboID proximity labeling followed by label-free quantitative proteomics in mouse brain neurons; proximity ligation assay validation bioRxivpreprint Low
2020 Computational atomistic modeling of the 5-phosphatase domain of synaptojanin-1 identified its active site and its binding mode to phosphatidylinositol 4,5-bisphosphate (PIP2); membrane-embedded molecular dynamics simulations suggested that a second divalent cation is required to complete dephosphorylation, defining structural requirements for catalysis. Homology modeling; membrane-embedded molecular dynamics simulation; active-site electrostatic analysis Computational and structural biotechnology journal Low 32419904

Source papers

Stage 0 corpus · 31 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2013 The Sac1 domain of SYNJ1 identified mutated in a family with early-onset progressive Parkinsonism with generalized seizures. Human mutation 274 23804563
2013 Mutation in the SYNJ1 gene associated with autosomal recessive, early-onset Parkinsonism. Human mutation 266 23804577
2014 PARK20 caused by SYNJ1 homozygous Arg258Gln mutation in a new Italian family. Neurogenetics 99 24816432
2016 Loss of SYNJ1 dual phosphatase activity leads to early onset refractory seizures and progressive neurological decline. Brain : a journal of neurology 71 27435091
2016 Identification of a novel homozygous mutation Arg459Pro in SYNJ1 gene of an Indian family with autosomal recessive juvenile Parkinsonism. Parkinsonism & related disorders 66 27496670
2014 Homozygous nonsense mutation in SYNJ1 associated with intractable epilepsy and tau pathology. Neurobiology of aging 59 25316601
2018 Alteration of endosomal trafficking is associated with early-onset parkinsonism caused by SYNJ1 mutations. Cell death & disease 57 29515184
2019 PERK-Mediated Unfolded Protein Response Activation and Oxidative Stress in PARK20 Fibroblasts. Frontiers in neuroscience 44 31316342
2001 Mutation analysis of SYNJ1: a possible candidate gene for chromosome 21q22-linked bipolar disorder. Molecular psychiatry 44 11443522
2018 A Novel SYNJ1 Mutation in a Tunisian Family with Juvenile Parkinson's Disease Associated with Epilepsy. Journal of molecular neuroscience : MN 31 30187305
2021 Clinical Variability of SYNJ1-Associated Early-Onset Parkinsonism. Frontiers in neurology 24 33841314
2019 A novel homozygous SYNJ1 mutation in two siblings with typical Parkinson's disease. Parkinsonism & related disorders 23 31751865
2023 Parkinsonism mutations in DNAJC6 cause lipid defects and neurodegeneration that are rescued by Synj1. NPJ Parkinson's disease 18 36739293
2004 Analysis of SYNJ1, a candidate gene for 21q22 linked bipolar disorder: a replication study. Psychiatry research 18 15261714
2017 SYNJ1 gene associated with neonatal onset of neurodegenerative disorder and intractable seizure. Molecular genetics & genomic medicine 17 29179256
2015 Mutational analysis of SYNJ1 gene (PARK20) in Parkinson's disease in a Taiwanese population. Neurobiology of aging 16 26149920
2021 ln RNA LINC01234 promotes triple-negative breast cancer progression through regulating the miR-429/SYNJ1 axis. American journal of translational research 14 34786067
2018 Clonazepam improves the symptoms of two siblings with novel variants in the SYNJ1 gene. Parkinsonism & related disorders 14 30473187
2021 MicroRNA expression profiling after recurrent febrile seizures in rat and emerging role of miR-148a-3p/SYNJ1 axis. Scientific reports 10 33441699
2021 RAB5C, SYNJ1, and RNF19B promote male ankylosing spondylitis by regulating immune cell infiltration. Annals of translational medicine 8 34277811
2020 Electroclinical Findings of SYNJ1 Epileptic Encephalopathy. Journal of pediatric neurosciences 8 32435303
2021 Temporal Vestibular Deficits in synaptojanin 1 (synj1) Mutants. Frontiers in molecular neuroscience 7 33584199
2015 Non-motor symptoms and cardiac innervation in SYNJ1-related parkinsonism. Parkinsonism & related disorders 7 26725142
2022 Down Syndrome Fetal Fibroblasts Display Alterations of Endosomal Trafficking Possibly due to SYNJ1 Overexpression. Frontiers in genetics 4 35646085
2024 Identification of SYNJ1 in a Complex Case of Juvenile Parkinsonism Using a Multiomics Approach. International journal of molecular sciences 3 39273702
2023 SYNJ1 rescues motor functions in hereditary and sporadic Parkinson's disease mice by upregulating TSP-1 expression. Behavioural brain research 3 37419331
2024 Co-occurrence of PRKN and SYNJ1 variants in Early-Onset Parkinson's disease. Metabolic brain disease 2 38836947
2020 Combining data integration and molecular dynamics for target identification in α-Synuclein-aggregating neurodegenerative diseases: Structural insights on Synaptojanin-1 (Synj1). Computational and structural biotechnology journal 2 32419904
2015 Olfaction in Homozygous and Heterozygous SYNJ1 Arg258Gln Mutation Carriers. Movement disorders clinical practice 2 30363595
2023 Upregulation of Heat-Shock Protein (hsp)-27 in a Patient with Heterozygous SPG11 c.1951C>T and SYNJ1 c.2614G>T Mutations Causing Clinical Spastic Paraplegia. Genes 1 37510225
2023 Analysis of differentially expressed genes discovers Latroeggtoxin VI-induced changes and SYNJ1 as a main target in PC12 cells. BMC genomics 1 37667188

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