Mitochondrial dysfunction and decrease in body weight of a transgenic knock-in mouse model for TDP-43.

Area of Science:

• Neuroscience
• Genetics
• Molecular Biology

Background:

• TDP-43 pathology is a hallmark of amyotrophic lateral sclerosis (ALS) and frontotemporal lobar dementia (FTLD).
• Understanding TDP-43's role is crucial for developing effective treatments for these neurodegenerative diseases.

Purpose of the Study:

• To create a novel mouse model expressing human TDP-43 with an ALS-associated mutation (A315T).
• To investigate the resulting TDP-43 pathology, gene expression changes, and cellular phenotypes.

Main Methods:

• Recombinase-mediated cassette exchange was used to introduce human A315T TDP-43 cDNA into the mouse Tdp-43 locus.
• Analysis included body weight, insoluble TDP-43 protein levels, gene expression (splicing patterns, genome-wide), and transmission electron microscopy of neuronal mitochondria.

Main Results:

• Heterozygous TDP-43(A315TKi) mice showed elevated human TDP-43 and reduced endogenous mouse TDP-43, leading to weight loss and insoluble TDP-43 aggregation.
• Mitochondrial dysfunction was indicated by altered gene expression (decreased Parkin, CD36) and abnormal mitochondrial cristae in motor cortex neurons.
• A slight reduction in motor neurons was observed, with minimal motor impairment.

Conclusions:

• The TDP-43(A315TKi) mouse model recapitulates key aspects of TDP-43 proteinopathy relevant to ALS and FTLD.
• This model provides a valuable platform for studying early disease mechanisms and identifying potential genetic or environmental triggers for neurodegeneration.