Role of neurofilament NFL depletion in TDP-43-mediated pathogenesis
Project Overview
his proposal is based on our finding of substantial depletion of neurofilament synthesis in mouse models of ALS with abnormal accumulations of TDP-43, a hallmark of the disease. This is due to a selective block of NF-L synthesis on ribosome machinery that is explained by the binding of excess cytoplasmic TDP-43 to specific nucleotide sequences in the 3’ untranslated (3’UTR) region of NF-L mRNA. The depletion of NF-L levels in ALS may be the source of neuronal dysfunctions as NF-L is known to play crucial roles in dendritic structure of spinal neurons, radial growth of axons, nerve conductivity and in the function of brain synapses. Here our goal is to determine to what extent the neuronal loss of NF-L may contribute to symptom phenotypes and pathological changes in context of TDP-43 pathology. This will be done by boosting NF-L synthesis in two distinct mouse models of ALS with the use of a new viral vector to deliver neuronal expression of NF-L mRNA lacking the 3’UTR sequences recognized by TDP-43. It is expected that restoring NF-L synthesis will alleviate in part symptom phenotypes and pathological defects. This project will advance the understanding of disease mechanisms associated with TDP-43 pathology and it may potentially lead to development of new viral therapy for ALS.
Principal Investigator
Jean-Pierre Julien , Université Laval
Team Members
Angela Genge, McGill University
Partners and Donors
ALS Society of Canada