The lipid phosphatase Synaptojanin 1 undergoes a significant alteration in expression and solubility and is associated with brain lesions in Alzheimer’s disease

Abstract

Synaptojanin 1 (SYNJ1) is a brain-enriched lipid phosphatase critically involved in autophagosomal/endosomal trafficking, synaptic vesicle recycling and metabolism of phosphoinositides. Previous studies suggest that SYNJ1 polymorphisms have significant impact on the age of onset of Alzheimer's disease (AD) and that SYNJ1 is involved in amyloid-induced toxicity. Yet SYNJ1 protein level and cellular localization in post-mortem human AD brain tissues have remained elusive. This study aimed to examine whether SYNJ1 localization and expression are altered in postmortem AD brains. We found that SYNJ1 is accumulated in Hirano bodies, plaque-associated dystrophic neurites and some neurofibrillary tangles (NFTs). SYNJ1 immunoreactivity was higher in neurons and in the senile plaques in AD patients carrying one or two ApolipoproteinE (APOE) ε4 allele(s). In two large cohorts of APOE-genotyped controls and AD patients, SYNJ1 transcripts were significantly increased in AD temporal isocortex compared to control. There was a significant increase in SYNJ1 transcript in APOEε4 carriers compared to non-carriers in AD cohort. SYNJ1 was systematically co-enriched with PHF-tau in the sarkosyl-insoluble fraction of AD brain. In the RIPA-insoluble fraction containing protein aggregates, SYNJ1 proteins were significantly increased and observed as a smear containing full-length and cleaved fragments in AD brains. In vitro cleavage assay showed that SYNJ1 is a substrate of calpain, which is highly activated in AD brains. Our study provides evidence of alterations in SYNJ1 mRNA level and SYNJ1 protein degradation, solubility and localization in AD brains.

RAB5C, SYNJ1, and RNF19B promote male ankylosing spondylitis by regulating immune cell infiltration

“…The protein encoded by the SYNJ1 gene is a lipid phosphatase that is abundant in brain tissue and plays an important role in synaptic vesicle circulation and phosphatidylinositol metabolism (43). Previous studies have shown that SYNJ1 performs a critical regulatory role in the occurrence and development of various neurological diseases such as Alzheimer's disease and Parkinson's disease (44,45). Moreover, SYNJ1 also has an important regulatory effect on autophagy, and studies have shown that it is a regulatory factor with crucial involvement in the maturation of presynaptic terminal autophagosomes in Alzheimer's (46).…”

Identification of Genetic Markers and Immune Infiltration Characteristics of Alzheimer’s Disease Through Weighted Gene Co-expression Network Analysis

“…SYNJ1 immunoreactivity is elevated in neurons and senile plaques in alzheimer disease patients with one or two apolipoprotein (APOE) ε4 alleles. 26 Phosphatidylinositol phosphatase synaptic binding protein 1 (SYNJ1), which regulates synaptic function, has been found to be negatively related to expression of synaptophysin, in postmortem brains of adult patients with Down syndrome (DS/alzheimer disease), by Miranda professor's. In mouse models studied by Professor Miranda, SYNJ1 overexpressing mice showed age-related cognitive decline to the level of human sporadic alzheimer disease, which is caused by hippocampal hyperexcitability and spatial reproducibility deficits in the position field.…”

Dysregulation of Phosphoinositide 5-Phosphatases and Phosphoinositides in Alzheimer's Disease

“…SYNJ1 is expressed in neurons and is implicated in Aß toxicity (Berman et al, 2008 ), synaptic toxicity (McIntire et al, 2012 ) and Aß clearance (Zhu et al, 2013 ). The mRNA level of SYNJ1 is significantly upregulated in post-mortem AD brains in association with APOE genotype (Zhu et al, 2015 ; Ando et al, 2020 ). SYNJ1 protein undergoes a significant solubility change and is co-enriched with PHF-tau in the sarkosyl-insoluble fraction (Ando et al, 2020 ).…”

“…The mRNA level of SYNJ1 is significantly upregulated in post-mortem AD brains in association with APOE genotype (Zhu et al, 2015 ; Ando et al, 2020 ). SYNJ1 protein undergoes a significant solubility change and is co-enriched with PHF-tau in the sarkosyl-insoluble fraction (Ando et al, 2020 ). SYNJ1 immunoreactivity is detected in actin-positive Hirano bodies, some NFTs and plaque-associated dystrophic neurites in post-mortem human AD brains (Ando et al, 2020 ).…”

“…SYNJ1 protein undergoes a significant solubility change and is co-enriched with PHF-tau in the sarkosyl-insoluble fraction (Ando et al, 2020 ). SYNJ1 immunoreactivity is detected in actin-positive Hirano bodies, some NFTs and plaque-associated dystrophic neurites in post-mortem human AD brains (Ando et al, 2020 ). Such aberrant alteration of mRNA levels, protein localization, and protein solubility of SYNJ1 could be applied to establish a valid biomarker for AD.…”