| Autor: |
Quinn, James P., Ethier, Elizabeth C., Kandigian, Savannah E., Trombetta, Bianca A., Arnold, Steven E., Carlyle, Becky C. |
| Zdroj: |
Alzheimer's & Dementia: The Journal of the Alzheimer's Association; Dec2021 Supplement S3, Vol. 17 Issue 3, p1-1, 1p |
| Abstrakt: |
Background: The granin family of neurotransmitter‐like molecules, neuropeptides, are proteolytically processed into functional peptides, also known as proteoforms. This family contains secretogranin VII (VGF), which was highlighted by AMP‐AD as the most nominated potential therapeutic target for Alzheimer's disease (AD) due to its levels being decreased in CSF samples and brain sections from patients with AD. Full‐length granins and their proteoforms are involved in diverse neuronal and synaptic functions, but their physiological processing pathways, contribution to dementia pathogenesis and potential use as a biomarker of dementia remain understudied. This project investigated the proteolytic processing of granins in silico and in vitro to improve our understanding of whether specific granin proteoforms represent potential therapeutic targets and biomarkers of dementia. Method: Proteasix and the human protein atlas were used to identify brain‐expressed proteases that may produce granin proteoforms. These granin proteoforms had been previously identified by our group in the CSF of patients with AD and healthy controls using mass spectrometry. Links to dementia pathogenesis were assessed in the literature. Cleavage specificity was assessed using recombinant protein assays and overexpression of granins and proteases in immortalized cell lines. Analysis was performed using gel electrophoresis and immunoblotting with granin‐specific antibodies. Result: Using Proteasix and the human protein atlas; 29 proteases that potentially cleave granins were also identified as expressed in the brain and 22 of these had been previously linked to dementia pathogenesis. Assays using recombinant proteins and immortalized cell lines identified that five proteases involved in dementia pathophysiology, ADAMTS4, calpain‐1, cathepsin S, granzyme A and MMP‐3 cleaved granins into a plethora of different proteoforms. Further work using mass spectrometry is ongoing to map these proteoforms against those identified in the CSF samples. Conclusion: Our results show that granins are proteolytically processed by proteases involved in dementia pathophysiology. This work improves our mechanistic understanding of granin processing and further establishes their potential as biomarkers of synaptic health in dementia and potential therapeutic targets. [ABSTRACT FROM AUTHOR] |
| Databáze: |
Supplemental Index |
| Externí odkaz: |
|
