Microglial upregulation of progranulin as a marker of motor neuron degeneration.
Frontotemporal lobar degeneration (FTLD) and amyotrophic lateral sclerosis (ALS) are overlapping neurodegenerative disorders. Mutations in the growth factor progranulin (PGRN) gene cause FTLD, sometimes in conjunction with ALS; such mutations are also observed in some ALS patients. Most PGRN mutations underlying FTLD are null mutations that result in reduced PGRN levels. We investigated PGRN expression in human ALS and in mouse models of motor neuron degeneration. Progranulin plasma or CSF levels in newly diagnosed ALS patients did not differ from those in healthy or disease controls (PGRN mutation-negative FTLD and Alzheimer disease patients). In the mutant SOD1 mouse model of ALS, spinal cord PGRN levels were normal in presymptomatic animals but increased during the degenerative process. This increase in PGRN correlated with enhanced expression of PGRN in microglia. In CSF, PGRN levels were normal in presymptomatic and early symptomatic animals, but with disease progression, a raise in PGRN was detectable. These data indicate that upregulation of PGRN is a marker of the microglial response that occurs with progression in motor neuron diseases.
Vesalius Research Center, VIB, Leuven, Belgium.
Thomas
T
Philips
Louis
L
De Muynck
Hoai Nguyen Thi
HN
Thu
Bea
B
Weynants
Peter
P
Vanacker
Joke
J
Dhondt
Kristel
K
Sleegers
Helenius J
HJ
Schelhaas
Marcel
M
Verbeek
Rik
R
Vandenberghe
Raf
R
Sciot
Christine
C
Van Broeckhoven
Diether
D
Lambrechts
Fred
F
Van Leuven
Ludo
L
Van Den Bosch
Wim
W
Robberecht
Philip
P
Van Damme
D000328:Adult; D000368:Aged; D000690:Amyotrophic Lateral Sclerosis / Q000097:blood / Q000134:cerebrospinal fluid / Q000473:pathology; D000818:Animals; D015415:Biomarkers / Q000097:blood / Q000134:cerebrospinal fluid; D018450:Disease Progression; D005260:Female; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000096:biosynthesis* / Q000097:blood / Q000134:cerebrospinal fluid; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D017628:Microglia / Q000378:metabolism* / Q000473:pathology; D008875:Middle Aged; D016472:Motor Neuron Disease / Q000097:blood / Q000134:cerebrospinal fluid / Q000473:pathology; D009410:Nerve Degeneration / Q000097:blood* / Q000134:cerebrospinal fluid* / Q000473:pathology; D000077153:Progranulins; D015854:Up-Regulation / Q000502:physiology*
D015415:Biomarkers; C492314:GRN protein, human; D036341:Intercellular Signaling Peptides and Proteins; D000077153:Progranulins