Abstract
SummaryDespite intuitive insights into differential proteolysis of amyloid precursor protein (APP), the stochasticity behind local product formation through amyloidogenic pathway at individual synapses remain unclear. Here, we show that the major components of amyloidogenic machinery namely, APP and secretases are discretely organized into nanodomains of high local concentration compared to their immediate environment in functional zones of the synapse. Additionally, with the aid of multiple models of Alzheimer's disease (AD), we confirm that this discrete nanoscale chemical map of amyloidogenic machinery is altered at excitatory synapses. Furthermore, we provide realistic models of amyloidogenic processing in unitary vesicles originating from the endocytic zone of excitatory synapses. Thus, we show how an alteration in the stochasticity of synaptic nanoscale organization contributes to the dynamic range of C-terminal fragments β (CTFβ) production, defining the heterogeneity of amyloidogenic processing at individual synapses, leading to long-term synaptic deficits as seen in AD.
Highlights
Enzymatic hydrolysis of peptide bonds induces an irreversible alteration of the molecular structure and biological function of a protein
We show that the major components of amyloidogenic machinery namely, amyloid precursor protein (APP) and secretases are discretely organized into nanodomains of high local concentration compared to their immediate environment in functional zones of the synapse
We provide realistic models of amyloidogenic processing in unitary vesicles originating from the endocytic zone of excitatory synapses
Summary
Enzymatic hydrolysis of peptide bonds (proteolysis) induces an irreversible alteration of the molecular structure and biological function of a protein. Sequential proteolysis is a targeted event where multiple enzymes act one after another on a single substrate resulting in several proteoforms (Klein et al, 2018). These alterations of the substrate molecule are controlled both spatially and temporally such that a change in the combination of proteases can result in proteoforms with antagonistic properties. APP can be processed by both canonical and non-canonical secretases, resulting in numerous proteoforms, mediating distinct and even opposing functions (Muller et al, 2017)
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