Soluble sortilin is present in excess and positively correlates with progranulin in CSF of aging individuals.
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.
Department of Neuroscience, Mayo Clinic, Jacksonville, FL, USA; Department of Biomedicine, Aarhus University, Aarhus, Denmark; The Lundbeck Foundation Research Center, MIND, Aarhus, Denmark.
Simon
S
Molgaard
Department of Biomedicine, Aarhus University, Aarhus, Denmark; The Lundbeck Foundation Initiative for Integrative Psychiatric Research, iPSYCH, Aarhus, Denmark.
Ditte
D
Demontis
Department of Neuroscience, Mayo Clinic, Jacksonville, FL, USA.
Alexandra M
AM
Nicholson
Department of Neuroscience, Mayo Clinic, Jacksonville, FL, USA.
Nicole A
NA
Finch
Department of Neurology, Mayo Clinic, Rochester, MN, USA.
Ronald C
RC
Petersen
Department of Biomedicine, Aarhus University, Aarhus, Denmark; The Lundbeck Foundation Research Center, MIND, Aarhus, Denmark.
Claus M
CM
Petersen
Department of Neuroscience, Mayo Clinic, Jacksonville, FL, USA.
Rosa
R
Rademakers
Department of Neuroscience, Mayo Clinic, Jacksonville, FL, USA; Department of Biomedicine, Aarhus University, Aarhus, Denmark; The Lundbeck Foundation Research Center, MIND, Aarhus, Denmark; Danish Research Institute of Translational Neuroscience DANDRITE, Nordic EMBL Partnership, Aarhus, Denmark.
Anders
A
Nykjaer
Department of Neuroscience, Mayo Clinic, Jacksonville, FL, USA; Department of Biomedicine, Aarhus University, Aarhus, Denmark; The Lundbeck Foundation Research Center, MIND, Aarhus, Denmark. Electronic address: glerup@biomed.au.dk.
Simon
S
Glerup
D033942:Adaptor Proteins, Vesicular Transport / Q000097:blood / Q000134:cerebrospinal fluid / Q000235:genetics*; D000368:Aged; D000369:Aged, 80 and over; D000375:Aging / Q000097:blood / Q000134:cerebrospinal fluid / Q000235:genetics*; D015415:Biomarkers / Q000097:blood / Q000134:cerebrospinal fluid; D003718:Denmark; D005260:Female; D057174:Frontotemporal Lobar Degeneration / Q000235:genetics; D005838:Genotype; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000134:cerebrospinal fluid*; D016014:Linear Models; D008297:Male; D009154:Mutation; D020641:Polymorphism, Single Nucleotide; D000077153:Progranulins; D000099183:Sortilin
D033942:Adaptor Proteins, Vesicular Transport; D015415:Biomarkers; D036341:Intercellular Signaling Peptides and Proteins; D000077153:Progranulins; D000099183:Sortilin; C492314:GRN protein, human
Aging; Biomarker; Decoy receptor; ELISA; Frontotemporal lobar degeneration; Progranulin; Single nucleotide polymorphism; Sortilin