Basic Science and Pathogenesis.

Area of Science:

• Neuroscience
• Molecular Biology
• Genetics

Background:

• Alzheimer's Disease (AD) and Frontotemporal Dementia (FTD) are linked to TAR DNA binding protein (TDP-43) mislocalization.
• TDP-43 dysfunction disrupts RNA splicing, including Stathmin-2 (STMN2), leading to reduced functional protein and increased cryptic variants.
• This STMN2 loss of function (LOF) is hypothesized to contribute to the cognitive deficits in AD and FTD.

Purpose of the Study:

• To develop and validate a novel mouse model that accurately reflects human disease mechanisms in AD and FTD.
• To investigate the role of TDP-43 in STMN2 splicing and its contribution to neurodegenerative disease phenotypes.
• To establish a tool for studying therapies targeting TDP-43-related RNA processing defects.

Main Methods:

• Generated a humanized Stmn2 mouse model.
• Utilized adeno-associated virus (AAV) to deliver short-hairpin RNA (shRNA) targeting Tardbp in the central nervous system.
• Simultaneously modeled TDP-43 loss of function and aberrant Stmn2 splicing in vivo.

Main Results:

• TDP-43 knockdown was confirmed via reduced Tardbp RNA and TDP-43 protein levels.
• Aberrant splicing of endogenous mouse targets (Sortilin 1, Translin) and Stmn2 was observed.
• The results confirm Tdp-43 dependence for correct Stmn2 splicing in this model.

Conclusions:

• The novel mouse model accurately recapitulates TDP-43-related STMN2 splicing defects observed in human neurodegenerative diseases.
• This model provides a valuable platform for further investigation into disease mechanisms.
• The model will facilitate the development and testing of therapeutic strategies for AD and FTD.