PMID- 30525042
OWN - NLM
STAT- PubMed-not-MEDLINE
LR  - 20200930
IS  - 2296-889X (Print)
IS  - 2296-889X (Electronic)
IS  - 2296-889X (Linking)
VI  - 5
DP  - 2018
TI  - Loss of Ca(2+)/Calmodulin Dependent Protein Kinase Kinase 2 Leads to Aberrant 
      Transferrin Phosphorylation and Trafficking: A Potential Biomarker for 
      Alzheimer's Disease.
PG  - 99
LID - 10.3389/fmolb.2018.00099 [doi]
LID - 99
AB  - Ca(2+)/calmodulin-dependent protein kinase kinase 2 (CaMKK2) is a 
      serine/threonine kinase that is activated following an increase in the 
      intracellular Ca(2+) concentration and activates multiple signaling cascades that 
      control physiologically important neuronal processes. CaMKK2 has been implicated 
      in schizophrenia, bipolar disease, neurodegeneration, and cancer. Using 
      isoelectric focusing (IEF) and mass spectrometry-based proteomic analysis, it was 
      found that knockdown (KD) of CaMKK2 in cultured adult primary dorsal root 
      ganglion (DRG) neurons resulted in the reduction of transferrin (TF) 
      phosphorylation at multiple functionally relevant residues which corresponded to 
      loss of an acidic fraction (pH~3-4) of TF. In vitro studies using CRISPR/Cas9 
      based CaMKK2 knockout (KO) HEK293 and HepG2 cells lines validated previous 
      findings and revealed that loss of CaMKK2 interfered with TF trafficking and 
      turnover. TF is an iron transporter glycoprotein. Abnormal accumulation of iron 
      and/or deregulated Ca(2+) homeostasis leads to neurodegeneration in Alzheimer's 
      disease (AD). Therefore, it was hypothesized that aberrant CaMKK2 in AD may lead 
      to aberrant phosphorylated transferrin (P-TF: pH~3-4 fraction) which may serve as 
      a hallmark biomarker for AD. A significant reduction of P-TF in the brain and 
      serum of CaMKK2 KO mice and a triple-transgenic mouse model of AD (3xTg-AD) 
      supported this hypothesis. In addition, analysis of early (< 65 years) and 
      late-stage (>65 years) postmortem human AD cerebrospinal fluid (CSF) and serum 
      samples revealed that aberrant P-TF (pH~3-4 fraction) profile was associated with 
      both early and late-stage AD compared to age-matched controls. This indicates 
      P-TF (pH~3-4 fraction) profile may be useful as a minimally invasive biomarker 
      for AD. In addition, this study provides a link between aberrant CaMKK2 with TF 
      trafficking and turnover which provides a novel insight into the 
      neurodegeneration process.
FAU - Sabbir, Mohammad Golam
AU  - Sabbir MG
AD  - Division of Neurodegenerative Disorders, St. Boniface Hospital Albrechtsen 
      Research Centre, Winnipeg, MB, Canada.
LA  - eng
PT  - Journal Article
DEP - 20181120
PL  - Switzerland
TA  - Front Mol Biosci
JT  - Frontiers in molecular biosciences
JID - 101653173
PMC - PMC6256988
OTO - NOTNLM
OT  - CaMKK2
OT  - alzheimer's disease
OT  - biomarker
OT  - cerebrospinal fluid
OT  - phosphorylation
OT  - serum
OT  - trafficking
OT  - transferrin
EDAT- 2018/12/14 06:00
MHDA- 2018/12/14 06:01
PMCR- 2018/01/01
CRDT- 2018/12/08 06:00
PHST- 2018/08/14 00:00 [received]
PHST- 2018/10/25 00:00 [accepted]
PHST- 2018/12/08 06:00 [entrez]
PHST- 2018/12/14 06:00 [pubmed]
PHST- 2018/12/14 06:01 [medline]
PHST- 2018/01/01 00:00 [pmc-release]
AID - 10.3389/fmolb.2018.00099 [doi]
PST - epublish
SO  - Front Mol Biosci. 2018 Nov 20;5:99. doi: 10.3389/fmolb.2018.00099. eCollection 
      2018.