TDP-43 as a cerebrospinal fluid marker of amyotrophic lateral sclerosis

• Applicant: Professor Dr. Johannes Brettschneider
• Subject Area: Clinical Neurology; Neurosurgery and Neuroradiology
• Term: from 2011 to 2012
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 203301903

Amyotrophic lateral sclerosis (ALS) is the most frequent motor neuron disease. The 43-kDa TAR DNA-binding protein (TDP-43) was identified as the major disease protein in ubiquitinated neuronal inclusions in sporadic ALS. TDP-43 is involved in transcription, splicing regulation, microRNA processing, apoptosis, and stabilisation of messenger RNA. So far, the pathogenic mechanism of TDP-43 in ALS remains unresolved. ALS is characterized by a markedly heterogeneous clinical presentation with a wide range of survival times. The pathological determinants of disease progression remain poorly understood, and an important challenge is to develop an understanding of how disease expression is modified by endogenous factors. The discovery of biomarkers could support an early diagnosis of ALS, and could offer new insight into the pathological determinants of disease progression. Cerebrospinal fluid (CSF) is a promising source of biomarkers since the CSF compartment is in close anatomical relation to the brain and spinal cord, and could reflect biochemical changes related to the disease. As the major disease protein in sporadic ALS, TDP-43 is a promising candidate for the development of biomarker assays. So far, there is no study analyzing CSF TDP-43 in a large cohort of ALS and relating it to different clinical phenotypes. We aim to develop a highly sensitive TDP-43 sandwich ELISA for analysis of CSF to determine whether CSF TDP-43 is of utility as a diagnostic and subtype specific biomarker of ALS. To achieve this aim, we will implement a panel of polyclonal antibodies and monoclonal antibodies to normal and pathological TDP-43 that detect epitopes spanning various regions of TDP-43, as well as those to specific phosphorylated residues. We will develop an assay optimized for analysis of CSF. Thereby, we aim to determine whether CSF concentrations of TDP-43 support the diagnosis of ALS, correspond to different clinical phenotypes and are associated with progression of disease.

• DFG Programme: Research Fellowships
• International Connection: USA
• Hosts: Professorin Dr. Virginia Lee, Ph.D.; Professor Dr. John Trojanowski, Ph.D. (†)