Previous studies have suggested that rare biallelic SYNJ1 mutations may cause autosomal recessive parkinsonism and Parkinson\'s disease (PD). Our study explored the impact of rare SYNJ1 variants in non-familial settings, including 8,165 PD cases, 818 early-onset PD (EOPD, <50 years) and 70,363 controls. Burden meta-analysis using optimized sequence Kernel association test (SKAT-O) revealed an association between rare nonsynonymous variants in the Sac1 SYNJ1 domain and PD (Pfdr=0.040). Additionally, a meta-analysis focusing on patients with EOPD demonstrated an association between all rare SYNJ1 variants and PD (Pfdr=0.029). Rare SYNJ1 variants may be associated with sporadic PD, and more specifically with EOPD.

UNASSIGNED: Network pharmacology and molecular docking were used to predict endogenous active metabolites with protective effects in diabetic kidney disease (DKD).
UNASSIGNED: We utilized metabolomics to screen differentially expressed metabolites in kidney tissues of mice with type 2 DKD and predicted potential targets using relevant databases. The interaction network between endogenous active metabolites and target proteins was established by integrating differentially expressed metabolites and proteins associated with DKD identified through proteomics. Gene ontology (GO) and signaling pathway enrichment analysis were performed. The biological functions of the active candidate metabolites and their effects on downstream pathways were also verified.
UNASSIGNED: Metabolomics revealed 130 differentially expressed metabolites. Through co-expression network analysis coupled with the investigation of differentially expressed proteins in proteomics, 2-hydroxyphenylpropionylglycine (2-HPG) emerged as a key regulator of DKD. 2-HPG was found to modulate the progression of DKD by regulating the conformation and activity of synaptophysin 1 (SYNJ1), with a correlation coefficient of 0.974. In vivo experiments revealed that SYNJ1 expression was significantly downregulated in the Macroalbuminuria Group compared to the Control Group and negatively correlated with proteinuria (r = -0.7137), indicating its important role in DKD progression. Immunofluorescence demonstrated that treatment with 2-HPG restores the expression of the foot process marker protein Wilms tumor-1 (WT-1) in podocytes injured by high glucose levels. Western blot and polymerase chain reaction support the involvement of SYNJ1 in this process.
UNASSIGNED: This study demonstrated the significance of the 2-HPG/SYNJ1 signaling axis in safeguarding the foot process of podocytes in DKD.

Apolipoprotein E epsilon 4 (ApoE4) is the second most common variant of ApoE, being present in ∼14% of the population. Clinical reports identify ApoE4 as a genetic risk factor for poor outcomes after traumatic spinal cord injury (SCI) and spinal cord diseases such as cervical myelopathy. To date, there is no intervention to promote recovery of function after SCI/spinal cord diseases that is specifically targeted at ApoE4-associated impairment. Studies in the human and mouse brain link ApoE4 to elevated levels of synaptojanin 1 (synj1), a lipid phosphatase that degrades phosphoinositol 4,5-bisphosphate (PIP2) into inositol 4-monophosphate. Synj1 regulates rearrangements of the cytoskeleton as well as endocytosis and trafficking of synaptic vesicles. We report here that, as compared to ApoE3 mice, levels of synj1 messenger RNA and protein were elevated in spinal cords of healthy ApoE4 mice associated with lower PIP2 levels. Using a moderate-severity model of contusion SCI in mice, we found that genetic reduction of synj1 improved locomotor function recovery at 14 days after SCI in ApoE4 mice without altering spared white matter. Genetic reduction of synj1 did not alter locomotor recovery of ApoE3 mice after SCI. Bulk RNA sequencing revealed that at 14 days after SCI in ApoE4 mice, genetic reduction of synj1 upregulated genes involved in glutaminergic synaptic transmission just above and below the lesion. Overall, our findings provide evidence for a link between synj1 to poor outcomes after SCI in ApoE4 mice, up to 14 days post-injury, through mechanisms that may involve the function of excitatory glutaminergic neurons.

This study aimed to explore the role of SYNJ1 in Parkinson\'s disease (PD) and its potential as a neuroprotective factor. We found that SYNJ1 was decreased in the SN and striatum of hSNCA*A53T-Tg and MPTP-induced mice compared to normal mice, associated with motor dysfunction, increased α-synuclein and decreased tyrosine hydroxylase. To investigate its neuroprotective effects, SYNJ1 expression was upregulated in the striatum of mice through injection of the rAdV-Synj1 virus into the striatum, which resulted in the rescue of behavioral deficiencies and amelioration of pathological changes. Subsequently, transcriptomic sequencing, bioinformatics analysis and qPCR were conducted in SH-SY5Y cells following SYNJ1 gene knockdown to identify its downstream pathways, which revealed decreased expression of TSP-1 involving extracellular matrix pathways. The virtual protein-protein docking further suggested a potential interaction between the SYNJ1 and TSP-1 proteins. This was followed by the identification of a SYNJ1-dependent TSP-1 expression model in two PD models. The coimmunoprecipitation experiment verified that the interaction between SYNJ1 and TSP-1 was attenuated in 11-month-old hSNCA*A53T-Tg mice compared to normal controls. Our findings suggest that overexpression of SYNJ1 may protect hSNCA*A53T-Tg and MPTP-induced mice by upregulating TSP-1 expression, which is involved in the extracellular matrix pathways. This suggests that SYNJ1 could be a potential therapeutic target for PD, though more research is needed to understand its mechanism.

Emerging evidence has illustrated that long noncoding RNA 01234 (LINC01234) has played a pivotal role in the development and progression of human cancer. The regulatory role and underlying mechanisms of LINC01234 in triple-negative breast cancer (TNBC) remains unknown. In this study, we analyzed the expression level of LINC01234 in several breast cancer cell lines. CCK-8, EdU, flow cytometry analysis, wound healing assay, and transwell assay were carried out to investigate the effect of LINC01234 on tumor proliferation, apoptosis, and migration. Bioinformatic analysis and luciferase reporter assays were performed to confirm the molecular binding. We found that LINC01234 was dramatically upregulated in breast cancer cell lines, especially in TNBC. The loss and gain-of functional experiments revealed that LINC01234 significantly promoted proliferation, migration, and suppressed cell apoptosis of MDA-MB-231 cells in vitro and inhibited tumorigenesis in vivo. Mechanistic investigations demonstrated that LINC01234 might act as a competing endogenous RNA (ceRNA) for miR-429 to regulate the SYNJ1 expression. The effects of miR-429 and SYNJ1 in MDA-MB-231 cells were also analyzed. Our results revealed that the novel LINC01234/miR-429/SYNJ1 axis played a critical role in progression of TNBC cell line MDA-MB-231, and it may serve as a therapeutic target for TNBC.

This mini-review aims to summarize a growing body of literature on synaptojanin 1 (Synj1), a phosphoinositide phosphatase that was initially known to have a prominent role in synaptic vesicle recycling. Synj1 is coded by the SYNJ1 gene, whose mutations and variants are associated with an increasing number of neurological disorders. To better understand the mechanistic role of Synj1 in disease pathogenesis, we review details of phosphoinositide signaling pathways and the reported involvement of Synj1 in membrane trafficking with a specific focus on Parkinson\'s disease (PD). Recent studies have tremendously advanced our understanding of Synj1 protein structure and function while broadening our view of how Synj1 regulates synaptic membrane trafficking and endosomal trafficking in various organisms and cell types. A growing body of evidence points to inefficient membrane trafficking as key pathogenic mechanisms in neurodegenerative diseases associated with abnormal Synj1 expression. Despite significant progress made in the field, the mechanism by which Synj1 connects to trafficking, signaling, and pathogenesis is lacking and remains to be addressed.

UNASSIGNED: This study aimed to identify the key genes related to male ankylosing spondylitis (AS) and to analyze the role of immune cell infiltration in the pathological process of this disease.
UNASSIGNED: The AS dataset was downloaded from the Gene Expression Omnibus (GEO) public database, and the data of male healthy controls (M_HC) and male AS patients (M_AS) were extracted. R software was used to identify differentially expressed genes (DEGs). Functional and pathway enrichment analysis of the DEGs was performed. A protein-protein interaction (PPI) network was constructed, and the hub genes were screened out. All expression profile data were analyzed by weighted correlation network analysis (WGCNA) to screen out the hub genes, which were then intersected with the hub genes from the PPI network to obtain the key genes. Finally, the difference in immune cell infiltration in the two sets of samples was evaluated with CIBERSORT, and the correlation between the key genes and infiltrating immune cells was analyzed.
UNASSIGNED: A total of 689 DEGs were obtained, of which 395 genes were up-regulated and 294 genes were down-regulated. Functional and pathway enrichment analysis showed that DEGs were mainly enriched in pathways related to immune response. Based on the PPI analysis, five clusters with high scores were selected. Through WGCNA, 14 gene modules were obtained. The green module with the highest correlation was selected and intersected with the cluster previously obtained to obtain three key genes, RAB5C, SYNJ1, and RNF19B. Immune infiltration analysis found that monocytes and gamma delta T cells may be involved in the process of AS. Also, RAB5C, SYNJ1, and RNF19B are all related to increased levels of monocytes and macrophages.
UNASSIGNED: RAB5C, SYNJ1, and RNF19B are key DEGs expressed in M_AS and may play a role in the disease\'s occurrence and development through regulating immune cell functions.

Parkinson\'s disease (PD) is the second most common neurodegenerative disorder after Alzheimer\'s disease. It is a chronic and progressive disorder estimated to affect at least 4 million people worldwide. Although the etiology of PD remains unclear, it has been found that the dysfunction of synaptic vesicle endocytosis (SVE) in neural terminal happens before the loss of dopaminergic neurons. Recently, accumulating evidence reveals that the PD-linked synaptic genes, including DNAJC6, SYNJ1, and SH3GL2, significantly contribute to the disruptions of SVE, which is vital for the pathogenesis of PD. In addition, the proteins encoded by other PD-associated genes such as SNCA, LRRK2, PRKN, and DJ-1 also play key roles in the regulation of SVE. Here we present the facts about SVE-related genes and discussed their potential relevance to the pathogenesis of PD.

Autosomal recessive early-onset parkinsonism is clinically and genetically heterogeneous. Mutations of three genes, PRKN, PINK1, and DJ-1 cause pure phenotypes usually characterized by levodopa-responsive Parkinson\'s disease. By contrast, mutations of other genes, including ATP13A2, PLA2G6, FBXO7, DNAJC6, SYNJ1, VPS13C, and PTRHD1, cause rarer, more severe diseases with a poor response to levodopa, generally with additional atypical features. We performed data mining on a gene panel or whole-exome sequencing in 460 index cases with early-onset (≤ 40 years) Parkinson\'s disease, including 57 with autosomal recessive disease and 403 isolated cases. We identified two isolated cases carrying biallelic mutations of SYNJ1 (double-heterozygous p.D791fs/p.Y232H and homozygous p. Y832C mutations) and two siblings with the recurrent homozygous p.R258Q mutation. All four variants were absent or rare in the Genome Aggregation Database, were predicted to be deleterious on in silico analysis and were found to be highly conserved between species. The patient with both the previously unknown p.D791fs and p.Y232H mutations presented with dystonia-parkinsonism accompanied by a frontal syndrome and oculomotor disturbances at the age of 39. In addition, two siblings from an Algerian consanguineous family carried the homozygous p.R258Q mutation and presented generalized tonic-clonic seizures during childhood, with severe intellectual disability, followed by progressive parkinsonism during their teens. By contrast, the isolated patient with the homozygous p. Y832C mutation, diagnosed at the age of 20, had typical parkinsonism, with no atypical symptoms and slow disease progression. Our findings expand the mutational spectrum and phenotypic profile of SYNJ1-related parkinsonism.

Parkinson\'s disease (PD) is one of the most common neurodegenerative diseases, which is characterized by the loss of dopaminergic neurons in the nigrostriatal pathway. Synaptic dysfunction impairs dopamine turnover and contributes to the degeneration of dopaminergic neurons. However, the molecular mechanisms underlying synaptic dysfunction and dopaminergic neuronal vulnerability in PD are not clear. Here, we report that synaptojanin 1 (SYNJ1), a polyphosphoinositide phosphatase concentrated at nerve terminals, is a substrate of a cysteine proteinase, asparagine endopeptidase (AEP). SYNJ1 is cleaved by the cysteine proteinase AEP at N599 in the brains of PD patients. AEP-mediated cleavage of SYNJ1 disrupts neuronal phosphoinositide homeostasis and causes synaptic dysfunction. Overexpression of the AEP-generated fragments of SYNJ1 triggers synaptic dysfunction and the degeneration of dopaminergic neurons, inducing motor defects in the α-synuclein transgenic mice. Blockage of AEP-mediated cleavage of SYJN1 alleviates the pathological and behavioral defects in a mouse model of PD. Our results demonstrate that the fragmentation of SYNJ1 by AEP mediates synaptic dysfunction and dopaminergic neuronal degeneration in PD.