Project: Imaging heterogeneous TDP-43 neuropathologies

Acronym	ImageTDP43 (Reference Number: JPND2020-568-078)
Project Topic	A diverse range of human neurodegenerative diseases with severe clinical phenotypes are associated with the abnormal accumulation of the transactive response DNA binding protein 43 kDa (TDP-43). TDP-43 is both an RNA and DNA binding protein, and is associated with a number of cellular functions, including RNA processing, RNA transport, DNA damage repair, synaptic plasticity and organellar homeostasis. Abnormal accumulation of TDP-43 is generally associated with a loss of TDP-43 function. The prevalence and heterogeneity of TDP-43 neuropathologies is a new and rapidly expanding area of neurobiological research. One of the major clinical limitations in understanding and diagnosing TDP-43-related proteinopathies is the lack of suitable PET tracers for imaging TDP-43 accumulation in vivo. We propose to address this clinical need by: a) better characterizing the diverse forms of TDP-43 that accumulate in different diseases and b) developing potential PET ligands that discriminate between different forms of TDP-43. Our team has already mastered a number of methodologies that would allow us to succeed in these important goals. Crucially, we have already identified tool compounds to develop into prospective candidate TDP-43 PET tracers. These tool compounds will be applied to biochemically and structurally defined forms of TDP-43 and tested for their ability to bind to abnormal accumulates of TDP-43 in model systems and postmortem human brain samples. The best of these agents will be screened in vivo to identify one or more clinical candidates for TDP-43 PET imaging. Our studies will then culminate with a human TDP-43 PET imaging trial in familial FTLD subjects.
Network	JPND
Call	Novel Imaging and Brain Stimulation Methods and Technologies Related to Neurodegenerative Diseases

Project partner

Number	Name	Role	Country
1	Universität Zürich	Coordinator	Switzerland
2	Fondazione Santa Lucia	Partner	Italy
3	Skane Lans Landsting (Region Skåne)	Partner	Sweden
4	Erasmus Medisch Centrum	Partner	Netherlands