Identification of the novel activity-driven interaction between synaptotagmin 1 and presenilin 1 links calcium, synapse, and amyloid beta.
BMC Biol
; 14: 25, 2016 Mar 31.
Article
em En
| MEDLINE
| ID: mdl-27036734
ABSTRACT
BACKGROUND:
Synaptic loss strongly correlates with memory deterioration. Local accumulation of amyloid ß (Aß) peptide, and neurotoxic Aß42 in particular, due to abnormal neuronal activity may underlie synaptic dysfunction, neurodegeneration, and memory impairments. To gain an insight into molecular events underlying neuronal activity-regulated Aß production at the synapse, we explored functional outcomes of the newly discovered calcium-dependent interaction between Alzheimer's disease-associated presenilin 1 (PS1)/γ-secretase and synaptic vesicle proteins.RESULTS:
Mass spectrometry screen of mouse brain lysates identified synaptotagmin 1 (Syt1) as a novel synapse-specific PS1-binding partner that shows Ca(2+)-dependent PS1 binding profiles in vitro and in vivo. We found that Aß level, and more critically, conformation of the PS1 and the Aß42/40 ratio, are affected by Syt1 overexpression or knockdown, indicating that Syt1 and its interaction with PS1 might regulate Aß production at the synapse. Moreover, ß-secretase 1 (BACE1) stability, ß- and γ-secretase activity, as well as intracellular compartmentalization of PS1 and BACE1, but not of amyloid precursor protein (APP), nicastrin (Nct), presenilin enhancer 2 (Pen-2), or synaptophysin (Syp) were altered in the absence of Syt1, suggesting a selective effect of Syt1 on PS1 and BACE1 trafficking.CONCLUSIONS:
Our findings identify Syt1 as a novel Ca(2+)-sensitive PS1 modulator that could regulate synaptic Aß, opening avenues for novel and selective synapse targeting therapeutic strategies.Palavras-chave
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Peptídeos beta-Amiloides
/
Sinaptotagmina I
/
Presenilina-1
/
Doença de Alzheimer
/
Mapas de Interação de Proteínas
Tipo de estudo:
Diagnostic_studies
/
Prognostic_studies
Limite:
Animals
/
Humans
Idioma:
En
Ano de publicação:
2016
Tipo de documento:
Article