Synaptojanin-1

The apolipoprotein E4 (ApoE4) allele is the strongest genetic risk factor for developing sporadic Alzheimer’s disease (AD). However, the mechanisms underlying the pathogenic nature of ApoE4 are not well understood. In this study, we have found that ApoE proteins are critical determinants of brain phospholipid homeostasis and that the ApoE4 isoform is dysfunctional in this process. We have found that the levels of phosphoinositol biphosphate (PIP2) are reduced in postmortem human brain tissues of ApoE4 carriers, in the brains of ApoE4 knock-in (KI) mice, and in primary neurons expressing ApoE4 alleles compared with those levels in ApoE3 counterparts. These changes are secondary to increased expression of a PIP2-degrading enzyme, the phosphoinositol phosphatase synaptojanin 1 (synj1), in ApoE4 carriers. Genetic reduction of synj1 in ApoE4 KI mouse models restores PIP2 levels and, more important, rescues AD-related cognitive deficits in these mice. Further studies indicate that ApoE4 behaves similar to ApoE null conditions, which fails to degrade synj1 mRNA efficiently, unlike ApoE3 does. These data suggest a loss of function of ApoE4 genotype. Together, our data uncover a previously unidentified mechanism that links ApoE4-induced phospholipid changes to the pathogenic nature of ApoE4 in AD.

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Synaptojanin 1: localization on coated endocytic intermediates in nerve terminals and interaction of its 170 kDa isoform with Eps15

FEBS Letters ◽

10.1016/s0014-5793(97)01451-8 ◽

1997 ◽

Vol 419 (2-3) ◽

pp. 175-180 ◽

Cited By ~ 95

Author(s):

Christof Haffner ◽

Kohji Takei ◽

Hong Chen ◽

Niels Ringstad ◽

Amy Hudson ◽

...

Keyword(s):

Nerve Terminals ◽

Synaptojanin 1

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Screening Assay for Small-Molecule Inhibitors of Synaptojanin 1, a Synaptic Phosphoinositide Phosphatase

CrossRef Listing of Deleted DOIs ◽

10.1177/1087057113510177 ◽

2013 ◽

Vol 19 (4) ◽

pp. 585-594 ◽

Cited By ~ 4

Author(s):

Laura Beth J. McIntire ◽

Kyu-In Lee ◽

Belle Chang-Ileto ◽

Gilbert Di Paolo ◽

Tae-Wan Kim

Keyword(s):

Amyloid Β ◽

Receptor Trafficking ◽

Water Soluble ◽

Amyloid Β Peptide ◽

Screening Assay ◽

Vesicle Recycling ◽

Lipid Phosphatase ◽

Phosphoinositide Phosphatase ◽

Synaptojanin 1 ◽

Behavioral Impairments

Elevation of amyloid β-peptide (Aβ) is critically associated with Alzheimer disease (AD) pathogenesis. Aβ-induced synaptic abnormalities, including altered receptor trafficking and synapse loss, have been linked to cognitive deficits in AD. Recent work implicates a lipid critical for neuronal function, phosphatidylinositol-4,5-bisphosphate [PI(4,5)P2], in Aβ-induced synaptic and behavioral impairments. Synaptojanin 1 (Synj1), a lipid phosphatase mediating the breakdown of PI(4,5)P2, has been shown to play a role in synaptic vesicle recycling and receptor trafficking in neurons. Heterozygous deletion of Synj1 protected neurons from Aβ-induced synaptic loss and restored learning and memory in a mouse model of AD. Thus, inhibition of Synj1 may ameliorate Aβ-associated impairments, suggesting Synj1 as a potential therapeutic target. To this end, we developed a screening assay for Synj1 based on detection of inorganic phosphate liberation from a water-soluble, short-chain PI(4,5)P2. The assay displayed saturable kinetics and detected Synj1’s substrate preference for PI(4,5)P2 over PI(3,4,5)P3. The assay will enable identification of novel Synj1 inhibitors that have potential utility as chemical probes to dissect the cellular role of Synj1 as well as potential to prevent or reverse AD-associated synaptic abnormalities.

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Phosphatidylinositol-(4,5)-bisphosphate regulates clathrin-coated pit initiation, stabilization, and size

Molecular Biology of the Cell ◽

10.1091/mbc.e11-04-0362 ◽

2011 ◽

Vol 22 (14) ◽

pp. 2588-2600 ◽

Cited By ~ 85

Author(s):

Costin N. Antonescu ◽

François Aguet ◽

Gaudenz Danuser ◽

Sandra L. Schmid

Keyword(s):

Mammalian Cells ◽

Lipid Binding ◽

Coated Pits ◽

Inositol Phosphatase ◽

Major Mechanism ◽

Synaptojanin 1 ◽

Phosphatidylinositol 4 ◽

Sirna Knockdown ◽

Interfering Rna ◽

Pit Initiation

Clathrin-mediated endocytosis (CME) is the major mechanism for internalization in mammalian cells. CME initiates by recruitment of adaptors and clathrin to form clathrin-coated pits (CCPs). Nearly half of nascent CCPs abort, whereas others are stabilized by unknown mechanisms and undergo further maturation before pinching off to form clathrin-coated vesicles (CCVs). Phosphatidylinositol-(4,5)-bisphosphate (PIP2), the main lipid binding partner of endocytic proteins, is required for CCP assembly, but little is currently known about its contribution(s) to later events in CCV formation. Using small interfering RNA (siRNA) knockdown and overexpression, we have analyzed the effects of manipulating PIP2 synthesis and turnover on CME by quantitative total internal reflection fluorescence microscopy and computational analysis. Phosphatidylinositol-4-phosphate-5-kinase cannot be detected within CCPs but functions in initiation and controls the rate and extent of CCP growth. In contrast, the 5′-inositol phosphatase synaptojanin 1 localizes to CCPs and controls early stabilization and maturation efficiency. Together these results suggest that the balance of PIP2 synthesis in the bulk plasma membrane and its local turnover within CCPs control multiple stages of CCV formation.

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Synaptojanin family members are implicated in endocytic membrane traffic in yeast

Journal of Cell Science ◽

10.1242/jcs.111.22.3347 ◽

1998 ◽

Vol 111 (22) ◽

pp. 3347-3356 ◽

Cited By ~ 2

Author(s):

B. Singer-Kruger ◽

Y. Nemoto ◽

L. Daniell ◽

S. Ferro-Novick ◽

P. De Camilli

Keyword(s):

Synaptic Vesicles ◽

Direct Evidence ◽

Family Members ◽

Fluid Phase ◽

Growth Defect ◽

Temperature Sensitive ◽

Close Link ◽

Fluid Phase Endocytosis ◽

Synaptojanin 1

The synaptojanins represent a subfamily of inositol 5′-phosphatases that contain an NH2-terminal Sac1p homology domain. A nerve terminal-enriched synaptojanin, synaptojanin 1, was previously proposed to participate in the endocytosis of synaptic vesicles and actin function. The genome of Saccharomyces cerevisiae contains three synaptojanin-like genes (SJL1, SJL2 and SJL3), none of which is essential for growth. We report here that a yeast mutant lacking SJL1 and SJL2 (Deltasjl1 Deltasjl2) exhibits a severe defect in receptor-mediated and fluid-phase endocytosis. A less severe endocytic defect is present in a Deltasjl2 Deltasjl3 mutant, while endocytosis is normal in a Deltasjl1 Deltasjl3 mutant. None of the mutants are impaired in invertase secretion. The severity of the endocytic impairment of the sjl double mutants correlates with the severity of actin and polarity defects. Furthermore, the deletion of SJL1 suppresses the temperature-sensitive growth defect of sac6, a mutant in yeast fimbrin, supporting a role for synaptojanin family members in actin function. These findings provide a first direct evidence for a role of synaptojanin family members in endocytosis and provide further evidence for a close link between endocytosis and actin function.

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