Limited role of free TDP-43 as a diagnostic tool in neurodegenerative diseases.
TAR DNA-binding protein 43 (TDP-43) is one of the neuropathological hallmarks in amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD). It is present in patients' blood and cerebrospinal fluid (CSF); however, the source and clinical relevance of TDP-43 measurements in body fluids is uncertain. We investigated paired CSF and serum samples, blood lymphocytes, brain urea fractions and purified exosomes from CSF for TDP-43 by one- (1D), and two-dimensional (2D) Western immunoblotting (WB) and quantitative mass spectrometry (MRM) in patients with ALS, FTLD and non-neurodegenerative diseases. By means of 2D-WB we were able to demonstrate a similar isoform pattern of TDP-43 in lymphocytes, serum and CSF in contrast to that of brain urea fractions with TDP-43 pathology. We found that the TDP-43 CSF to blood concentration ratio is about 1:200. As a possible brain specific fraction we found TDP-43 in exosome preparations from CSF by immunoblot and MRM. We conclude that TDP-43 in CSF originates mainly from blood. Measurements of TDP-43 in CSF and blood are of minor importance as a diagnostic tool, but may be important for monitoring therapy effects of TDP-43 modifying drugs.
Department of Neurology, University of Ulm , Ulm.
Emily
E
Feneberg
Petra
P
Steinacker
Stefan
S
Lehnert
Anja
A
Schneider
Paul
P
Walther
Dietmar R
DR
Thal
Miriam
M
Linsenmeier
Albert C
AC
Ludolph
Markus
M
Otto
D000368:Aged; D004268:DNA-Binding Proteins / Q000097:blood* / Q000134:cerebrospinal fluid* / Q000648:ultrastructure; D055354:Exosomes / Q000378:metabolism / Q000648:ultrastructure; D005260:Female; D006801:Humans; D008214:Lymphocytes / Q000378:metabolism; D008297:Male; D013058:Mass Spectrometry; D008565:Membrane Proteins / Q000378:metabolism; D046529:Microscopy, Electron, Transmission; D008875:Middle Aged; D008970:Molecular Weight; D019636:Neurodegenerative Diseases / Q000097:blood / Q000134:cerebrospinal fluid* / Q000175:diagnosis
D004268:DNA-Binding Proteins; D008565:Membrane Proteins; C106354:flotillins
TDP-43; amyotrophic lateral sclerosis; biomarker; cerebrospinal fluid; exosomes; frontotemporal lobar degeneration