Challenges of modelling TDP-43 pathology in mice.

Area of Science:

• Neuroscience
• Molecular Biology
• Genetics

Background:

• TDP-43 is a nuclear RNA-binding protein.
• Pathological TDP-43 is found in the cytoplasm as insoluble inclusions.
• This TDP-43 pathology is a common feature in amyotrophic lateral sclerosis (ALS), limbic-predominant age-related TDP-43 encephalopathy (LATE), frontotemporal lobar degeneration (FTLD), and Alzheimer's disease (AD).

Purpose of the Study:

• To review existing mouse models of TDP-43 pathology.
• To discuss models with genetic mutations causing TDP-43 pathology.
• To explore strategies for developing new models to study TDP-43's nuclear-to-cytoplasmic transition and its disease implications.

Main Methods:

• Discussion of genetic mouse models exhibiting TDP-43 pathology.
• Consideration of models where TDP-43 pathology arises from mutations in other genes.
• Review of experimental manipulations to induce TDP-43 pathology.

Main Results:

• TDP-43 pathology is present in various genetic mouse models.
• Mutations in different genes can lead to TDP-43 pathology.
• Current models face challenges in replicating both nuclear loss-of-function and cytoplasmic accumulation of TDP-43.

Conclusions:

• TDP-43 pathology is a shared mechanism in diverse neurodegenerative diseases.
• Accurate modeling of TDP-43 pathology, including nuclear export and cytoplasmic aggregation, is crucial.
• Further development of mouse models is needed to understand the mechanisms and consequences of TDP-43 mislocalization.