Corticospinal tract degeneration in a TDP-43 transgenic mouse model of ALS/FTD: application of 3D reconstruction in cleared tissue

H.R QUINTÁ; L MULLER IGAZ

Congreso; International Conference on Neurology &Neurological Disorder; 2023

The neurodegenerative diseases amyotrophic lateral sclerosis (ALS) and frontotemporaldementia (FTD) represent two ends of one spectrum disorder, termed ALS/FTD. Theseincurable pathologies are now classified as “TDP-43 proteinopathies”, sincemislocalization and aggregation of the nuclear protein TDP-43 are hallmark features ofmost cases. A main feature of ALS/FTD is degeneration of the corticospinal tract (CST),composed of axons of upper motor neurons, being the main motor pathway involved involuntary movement. We are using a novel approach, combining a cost-effectiveunsectioned brain/spinal cord clearing technique, fluoroRuby staining, one-photon confocalmicroscopy and 3D reconstruction to study the morphological changes in the CST of TDP-43 transgenic (TG) mice. We have previously shown in mice that inducible overexpressionof a cytoplasmic (ΔNLS) form of TDP-43 in forebrain neurons evokes neuropathologicaland behavioural changes that recapitulate several features of TDP-43 proteinopathies. Ourpreliminary results showed proper and consistent tracer delivery, with similar number oflabelled cortical neurons in control and TG mice. TDP-43-ΔNLS expression decreased thelength of cortical apical processes and the number of cervical axons. Remarkably,suppression of TG expression (displaying reversible motor phenotypes) led to an increasein cervical axonal branching. These studies will help to elucidate the mechanismsunderlying the motor phenotypes in ALS/FTD.