Claus Munck Petersen

Soluble sortilin is present in excess and positively correlates with progranulin in CSF of aging individuals

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  • Simon Molgaard
  • Ditte Demontis
  • Alexandra M Nicholson, The Lundbeck Foundation Research Center MIND, Department of Biomedicine, Aarhus University, Aarhus, 8000 C, Denmark ; Department of Neuroscience, Mayo Clinic, Jacksonville, FL, FL 32224, USA ; Danish Research Institute of Translational Neuroscience DANDRITE, Aarhus, 8000, Denmark.
  • ,
  • Nicole A Finch, The Lundbeck Foundation Research Center MIND, Department of Biomedicine, Aarhus University, Aarhus, 8000 C, Denmark ; Department of Neuroscience, Mayo Clinic, Jacksonville, FL, FL 32224, USA ; Danish Research Institute of Translational Neuroscience DANDRITE, Aarhus, 8000, Denmark.
  • ,
  • Ronald C Petersen, Department of Neurology, Mayo Clinic, Rochester, MN, USA. dyck.peter@mayo.edu.
  • ,
  • Claus M Petersen
  • Rosa Rademakers, The Lundbeck Foundation Research Center MIND, Department of Biomedicine, Aarhus University, Aarhus, 8000 C, Denmark ; Department of Neuroscience, Mayo Clinic, Jacksonville, FL, FL 32224, USA ; Danish Research Institute of Translational Neuroscience DANDRITE, Aarhus, 8000, Denmark.
  • ,
  • Anders Nykjaer
  • Simon Glerup

Mutations in progranulin are a major cause of frontotemporal lobe degeneration (FTLD). Hence, plasma progranulin is an attractive biomarker in FTLD but poorly reflects levels in cerebrospinal fluid (CSF), suggesting tissue-specific regulation of progranulin levels. Sortilin was recently identified as a progranulin scavenger receptor that destines it for lysosomal degradation. Proteolysis or alternative splicing generates soluble sortilin variants that retain progranulin binding and potentially functions as a decoy receptor. In the present study, we analyzed soluble sortilin and progranulin in plasma and CSF in 341 aging individuals. We found that soluble sortilin exists in CSF in ten-fold molar excess compared to progranulin and observed a highly significant positive correlation between soluble sortilin and progranulin levels in CSF but not in plasma. However, carriers of the minor allele of SNP rs646776 in SORT1 encoding sortilin displayed significantly increased soluble sortilin and reduced progranulin specifically in plasma but not in CSF. Taken together, our findings suggest that soluble sortilin may affect progranulin levels in both a tissue-specific and genotype-dependent manner.

Original languageEnglish
JournalExperimental Gerontology
Volume84
Pages (from-to)96-100
Number of pages5
ISSN0531-5565
DOIs
Publication statusPublished - Nov 2016

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