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

2013 ◽  
Vol 19 (4) ◽  
pp. 585-594 ◽  
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.

scholarly journals Heterogeneity of water-soluble amyloid β-peptide in Alzheimer's disease and Down's syndrome brains

FEBS Letters ◽  
1997 ◽  
Vol 409 (3) ◽  
pp. 411-416 ◽  
Author(s):  
Claudio Russo ◽  
Takaomi C. Saido ◽  
Laura M. DeBusk ◽  
Massimo Tabaton ◽  
Pierluigi Gambetti ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Down's Syndrome ◽  
Amyloid Β ◽  
Down’S Syndrome ◽  
Water Soluble ◽  
Amyloid Β Peptide

Use of a new water-soluble Zn sensor to determine Zn affinity for the amyloid-β peptide and relevant mutants

Metallomics ◽  
2014 ◽  
Vol 6 (7) ◽  
pp. 1220 ◽  
Author(s):  
Sabrina Noël ◽  
Susana Bustos Rodriguez ◽  
Stéphanie Sayen ◽  
Emmanuel Guillon ◽  
Peter Faller ◽  
...  
Keyword(s):  
Amyloid Β ◽  
Water Soluble ◽  
Amyloid Β Peptide

Controlled Production of Amyloid β Peptide from a Photo-Triggered, Water-Soluble Precursor “Click Peptide“

ChemBioChem ◽  
2008 ◽  
Vol 9 (18) ◽  
pp. 3055-3065 ◽  
Author(s):  
Atsuhiko Taniguchi ◽  
Mariusz Skwarczynski ◽  
Youhei Sohma ◽  
Takuma Okada ◽  
Keisuke Ikeda ◽  
...  
Keyword(s):  
Amyloid Β ◽  
Water Soluble ◽  
Amyloid Β Peptide

Inhibition of Aβ(1–40) fibril formation by cyclophilins

2016 ◽  
Vol 473 (10) ◽  
pp. 1355-1368 ◽  
Author(s):  
Marten Villmow ◽  
Monika Baumann ◽  
Miroslav Malesevic ◽  
Rolf Sachs ◽  
Gerd Hause ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Amyloid Β ◽  
Fibril Formation ◽  
Water Soluble ◽  
Main Process ◽  
Amyloid Β Peptide ◽  
Cyclophilin D ◽  
Aβ Amyloid

Cyclophilins interact directly with the Alzheimer's disease peptide Aβ (amyloid β-peptide) and are therefore involved in the early stages of Alzheimer's disease. Aβ binding to CypD (cyclophilin D) induces dysfunction of human mitochondria. We found that both CypD and CypA suppress in vitro fibril formation of Aβ(1–40) at substoichiometric concentrations when present early in the aggregation process. The prototypic inhibitor CsA (cyclosporin A) of both cyclophilins as well as the new water-soluble MM258 derivative prevented this suppression. A SPOT peptide array approach and NMR titration experiments confirmed binding of Aβ(1–40) to the catalytic site of CypD mainly via residues Lys16–Glu22. The peptide Aβ(16–20) representing this section showed submicromolar IC50 values for the peptidyl prolyl cis–trans isomerase activity of CypD and CypA and low-micromolar KD values in ITC experiments. Chemical cross-linking and NMR-detected hydrogen–deuterium exchange experiments revealed a shift in the populations of small Aβ(1–40) oligomers towards the monomeric species, which we investigated in the present study as being the main process of prevention of Aβ fibril formation by cyclophilins.

scholarly journals Preparation and photo-induced activities of water-soluble amyloid β-C60 complexes

RSC Advances ◽  
2018 ◽  
Vol 8 (32) ◽  
pp. 17847-17853 ◽  
Author(s):  
Naoki Hasunuma ◽  
Masahiro Kawakami ◽  
Hirotsugu Hiramatsu ◽  
Takakazu Nakabayashi
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Amyloid Β ◽  
Water Soluble ◽  
Amyloid Β Peptide

We have shown that fullerene (C60) becomes soluble in water by mixing fullerene and amyloid β peptide (Aβ40) whose fibril structures are considered to be associated with Alzheimer's disease.

scholarly journals Absence of Sac2/INPP5F enhances the phenotype of a Parkinson’s disease mutation of synaptojanin 1

2020 ◽  
Author(s):  
Mian Cao ◽  
Daehun Park ◽  
Yumei Wu ◽  
Pietro De Camilli
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Gene Encoding ◽  
Phosphatase Domain ◽  
Stunted Growth ◽  
Inositol Phosphatase ◽  
Vesicle Recycling ◽  
Phosphoinositide Phosphatase ◽  
Abnormal Accumulation ◽  
Synaptojanin 1

AbstractMany genes whose mutations cause, or increase the risk of, Parkinson’s disease (PD) have been identified. An inactivating mutation (R258Q) in the Sac inositol phosphatase domain of synaptojanin 1 (SJ1/PARK20), a phosphoinositide phosphatase implicated in synaptic vesicle recycling, results in PD. The gene encoding Sac2/INPP5F, another Sac domain containing protein, was identified as a PD risk locus by GWAS. Knock-In mice carrying the SJ1 patient mutation (SJ1RQKI) exhibit PD features, while Sac2 knockout mice (Sac2KO) do not have obvious neurological defects. We report a “synthetic” effect of the SJ1 mutation and the KO of Sac2 in mice. Most mice with both mutations died perinatally. The occasional survivors had stunted growth, died within 3 weeks, and showed abnormalities of striatal dopaminergic nerve terminals at an earlier stage than SJ1RQKI mice. The abnormal accumulation of endocytic factors observed at synapses of cultured SJ1RQKI neurons was more severe in double mutant. Our results suggest that SJ1 and Sac2 have partially overlapping functions and are consistent with a potential role of Sac2 as a PD risk gene.

Amyloid β-peptide and Alzheimer's disease

2014 ◽  
Vol 56 ◽  
pp. 99-110 ◽  
Author(s):  
David Allsop ◽  
Jennifer Mayes
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Senile Plaques ◽  
Strong Support ◽  
Amyloid Β ◽  
Amyloid Β Peptide ◽  
Amyloid Cascade Hypothesis ◽  
Sequence Of Events ◽  
Aβ Amyloid ◽  
Amyloid Cascade

One of the hallmarks of AD (Alzheimer's disease) is the formation of senile plaques in the brain, which contain fibrils composed of Aβ (amyloid β-peptide). According to the ‘amyloid cascade’ hypothesis, the aggregation of Aβ initiates a sequence of events leading to the formation of neurofibrillary tangles, neurodegeneration, and on to the main symptom of dementia. However, emphasis has now shifted away from fibrillar forms of Aβ and towards smaller and more soluble ‘oligomers’ as the main culprit in AD. The present chapter commences with a brief introduction to the disease and its current treatment, and then focuses on the formation of Aβ from the APP (amyloid precursor protein), the genetics of early-onset AD, which has provided strong support for the amyloid cascade hypothesis, and then on the development of new drugs aimed at reducing the load of cerebral Aβ, which is still the main hope for providing a more effective treatment for AD in the future.

Insights into amyloid disease from fly models

2014 ◽  
Vol 56 ◽  
pp. 69-83 ◽  
Author(s):  
Ko-Fan Chen ◽  
Damian C. Crowther
Keyword(s):  
Drosophila Melanogaster ◽  
Neurodegenerative Disorders ◽  
Amyloid Β ◽  
Amyloid Β Peptide ◽  
Disease Pathogenesis ◽  
Amyloid Aggregates ◽  
Aβ Amyloid ◽  
Polypeptide Chains ◽  
Amyloid Diseases

The formation of amyloid aggregates is a feature of most, if not all, polypeptide chains. In vivo modelling of this process has been undertaken in the fruitfly Drosophila melanogaster with remarkable success. Models of both neurological and systemic amyloid diseases have been generated and have informed our understanding of disease pathogenesis in two main ways. First, the toxic amyloid species have been at least partially characterized, for example in the case of the Aβ (amyloid β-peptide) associated with Alzheimer's disease. Secondly, the genetic underpinning of model disease-linked phenotypes has been characterized for a number of neurodegenerative disorders. The current challenge is to integrate our understanding of disease-linked processes in the fly with our growing knowledge of human disease, for the benefit of patients.

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