Skip to content

Case study

ALS disease models and identification of molecular probes that modulate TDP-43

Lead PI: Dr Marco Baralle, International Centre for Genetics Engineering and Biotechnology, Italy.

Dementia Consortium funds project
Project reaches all milestones
Results published in Neurobiology of Disease

Collaboration agreement signed with MSD to further evaluate compounds identified in the screening campaign.
DCtimeline

2015

Dementia Consortium funds project

2019

Project reaches all milestones

2021

Results published in Neurobiology of Disease

Collaboration agreement signed with MSD to further evaluate compounds identified in the screening campaign.

Aberrant TDP-43 protein aggregation is the principal pathological mechanism behind amyotrophic lateral sclerosis (ALS) and the loss of TDP-43 function is detrimental in neurodegeneration. TDP-43 neuronal inclusions are also present in approximately one third of Alzheimer disease brains and TDP-43 protein depositions occur in other disorders. In Drosophila, the absence of TDP-43 orthologue (TBPH) results in a severe locomotion defect. This phenotype can be rescued even in late stages in the fly lifecycle, indicating that the defects produced by the lack of TDP-43 can be reversed. The project aims to develop a cell-based screen for compounds that reduce or clear TDP-43 aggregates and restore TDP-43 function, which will potentially lead to treatments for TDP-43 – related diseases.

Dr Marco Baralle

International Centre for Genetic Engineering and Biotechnology, Italy

“The Dementia Consortium has been essential in bringing my academic research to a level that would now be considered by companies working in early drug discovery. This has been done not only by providing the funding but as importantly creating and facilitating a network of collaborators that have contributed with ideas, expertise and project management”

Outcomes

1

Identified novel small molecule compounds that prevented TDP-43 inclusions, relevant for a number of disorders including ALS and Alzheimer’s disease

2

Identified novel small molecule compounds that prevented TDP-43 inclusions, relevant for a number of disorders including ALS and Alzheimer’s disease

3

Identified novel small molecule compounds that prevented TDP-43 inclusions, relevant for a number of disorders including ALS and Alzheimer’s disease

Publication

Cragnaz L, Spinelli G, De Conti L, Bureau EA, Brownlees J, Feiguin F, Romano V, Skoko N, Klima R, Kettleborough CA, Baralle FE, Baralle M. Thioridazine reverts the phenotype in cellular and Drosophila models of amyotrophic lateral sclerosis by enhancing TDP-43 aggregate clearance. Neurobiol Dis. 2021 Sep 24:105515.