In vivo modelling and therapy development for stathmin-2 loss in TDP-43 proteinopathies

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PROJECT SUMMARY TDP-43 proteinopathies represent a set of neurological disorders characterized by relocalization of the RNA- binding protein TDP-43 from its native nuclear compartment to the cytoplasm where it accumulates into aggregates. TDP-43 pathology is found in more than 95% of patients with amyotrophic lateral sclerosis (ALS), approximately half of frontotemporal dementia (FTD) cases, and more than 30% of Alzheimer’s disease patients. TDP-43 is involved in fundamental RNA processing activities and binds thousands of transcripts to regulate their expression, splicing and transport. We and others have recently identified a critical role for TDP-43 in regulating the expression of the neuronal growth-associated factor stathmin-2, a tubulin-binding protein involved in axon outgrowth and regeneration. TDP-43 disruption induces truncation (by aberrant splicing and premature polyadenylation) of stathmin-2 pre-mRNA, thereby silencing stathmin-2 when TDP-43 nuclear levels fall. Stathmin-2 is suppressed in affected neurons from the vast majority of ALS/FTD patients, and the neuronal regeneration capacity of iPSC-derived motor neurons with TDP-43 depletion can be rescued by increasing levels of STMN2. Notably, while stathmin-2 is the human mRNA most affected by reduction in TDP-43, the stahmin-2 pre-mRNA is neither bound nor regulated by TDP-43 in rodents, a major caveat for animal modeling of TDP-43 proteinopathies. Here we propose to use newly generated mouse models to determine whether inactivated (Aim 1) or humanized stathmin-2 (Aim 2) alleles synergize with TDP-43, progranulin, or C9ORF72 ALS/FTD mutations to drive motor neuron or cognitive disease. While evidence supports that stathmin-2 is essential for axonal regeneration, the contribution of stathmin-2 loss in neurodegeneration remains to be determined. We propose an ambitious program to establish the impact of in vivo stathmin-2 reduction in TDP-43 proteinopathies. Mouse models generated in this project will recapitulate a major molecular alteration associated with TDP-43 proteinopathy and represent an important platform for therapeutic development in ALS/FTD. In addition, recognizing that restoration of stathmin-2 level is an attractive strategy with broad implications in neurodegenerative diseases, we will test the therapeutic potential of antisense oligonucleotides (ASO) that prevent aberrant splicing of Stmn2 (Aim 3). This collaborative effort has the potential to uncover new insights on the contribution of stathmin-2 loss in neurodegeneration, to generate new preclinical models, and to develop a novel therapeutic strategy for ALS and FTD.