The lipid phosphatase Synaptojanin 1 undergoes a significant alteration in expression and solubility and is associated with brain lesions in Alzheimer\u2019s disease

Kunie Ando,Michèle Authelet,Sabrina Turbant,Marième Ndjim,Valérie Suain,Karelle Leroy,Gustavo Pregoni,Charles Duyckaerts,Salwa Mansour,Robert De Dekker,Benoı̂t Delatour ,Marie‐Claude Potier ,Luce Dauphinot,Zehra Yilmaz,G Fontaine ,Jean Pierre Brion

doi:10.1186/s40478-020-00954-1

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 post-mortem 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.

Highlights

Alzheimer disease (AD) is neuropathologically characterized by extracellular amyloid plaques composed of amyloid β (Aβ) peptides and intracellular neurofibrillary tangles (NFTs) constituted of microtubule associated protein tau
SYNJ1 is accumulated in neurons, plaque-associated dystrophic neurites and Hirano bodies in AD brains Five anti-SYNJ1 antibodies were characterized
(See figure on previous page.) Fig. 1 SYNJ1 is accumulated in neurons, Hirano bodies and plaque-associated dystrophic neurites in AD brains. a Immunostaining of SYNJ1 in hippocampal CA1–2 area of a control case carrying APOEε3/3

Summary

Introduction

Alzheimer disease (AD) is neuropathologically characterized by extracellular amyloid plaques composed of amyloid β (Aβ) peptides and intracellular neurofibrillary tangles (NFTs) constituted of microtubule associated protein tau. Several studies have shown that lipid phosphatase Synaptojanin (SYNJ1) is profoundly involved in human neurodegenerative diseases such as AD, early onset Parkinson’s disease (PD) and Down syndrome (DS). Human SYNJ1 mutations have been reported in familial PD: R268G substitution of SYNJ1 SAC1 domain was identified in early onset familial PD [29, 48, 50]. SYNJ1 expression is exacerbated in old individuals with Down syndrome with AD-like neuropathological lesions (DSAD) [38]. Whereas excessive Synj expression leads to memory deficits in rodent [59], homozygous Synj knockout mice are lethal [20] and a rare human homozygous nonsense mutation in SYNJ1 caused epilepsy and severe tau pathology in a young child [22]

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