A Novel Genetic TDP-43 Pig Model Mimics Multiple Key ALS-Like Features

Area of Science:

• Neuroscience
• Genetics
• Animal Models

Background:

• Amyotrophic lateral sclerosis (ALS) is a severe neurodegenerative disease with limited effective models.
• TDP-43 proteinopathy is a critical factor in ALS progression.
• Large animal models offer potential for better human disease simulation due to brain similarities.

Purpose of the Study:

• To establish a TDP-43-induced neurodegenerative disease model in pigs.
• To evaluate the utility of this porcine model for studying ALS pathogenesis and therapeutics.

Main Methods:

• Rapid establishment of a TDP-43-induced neurodegenerative disease model in pigs via viral vector delivery (TDP-43^M337V).
• Systematic evaluation using behavioral assessments and pathological analyses.
• Analysis of key protein markers (TMEM106B, SOD1, APOE4) and neuropathological features.

Main Results:

• The porcine model exhibited severe motor dysfunction, muscle atrophy, and fibrosis.
• Observed characteristic TDP-43 pathology, including spinal motor neuron degeneration and glial cell proliferation.
• Significant upregulation of TMEM106B, SOD1, and APOE4 levels was noted.

Conclusions:

• The TDP-43 porcine model effectively recapitulates critical features of Amyotrophic Lateral Sclerosis.
• This model serves as a valuable complement to existing ALS research models.
• It provides a robust platform for investigating TDP-43-related mechanisms and developing novel therapeutics.