Pathological hallmarks of amyotrophic lateral sclerosis/frontotemporal lobar degeneration in transgenic mice produced with TDP-43 genomic fragments.

Abstract

Transactive response DNA-binding protein 43 ubiquitinated inclusions are a hallmark of amyotrophic lateral sclerosis and of frontotemporal lobar degeneration with ubiquitin-positive inclusions. Yet, mutations in TARDBP, the gene encoding these inclusions are associated with only 3% of sporadic and familial amyotrophic lateral sclerosis. Recent transgenic mouse studies have revealed a high degree of toxicity due to transactive response DNA-binding protein 43 proteins when overexpressed under the control of strong neuronal gene promoters, resulting in early paralysis and death, but without the presence of amyotrophic lateral sclerosis-like ubiquitinated transactive response DNA-binding protein 43-positive inclusions. To better mimic human amyotrophic lateral sclerosis, we generated transgenic mice that exhibit moderate and ubiquitous expression of transactive response DNA-binding protein 43 species using genomic fragments that encode wild-type human transactive response DNA-binding protein 43 or familial amyotrophic lateral sclerosis-linked mutant transactive response DNA-binding protein 43 (G348C) and (A315T). These novel transgenic mice develop many age-related pathological and biochemical changes reminiscent of human amyotrophic lateral sclerosis including ubiquitinated transactive response DNA-binding protein 43-positive inclusions, transactive response DNA-binding protein 43 cleavage fragments, intermediate filament abnormalities, axonopathy and neuroinflammation. All three transgenic mouse models (wild-type, G348C and A315T) exhibited impaired learning and memory capabilities during ageing, as well as motor dysfunction. Real-time imaging with the use of biophotonic transactive response DNA-binding protein 43 transgenic mice carrying a glial fibrillary acidic protein-luciferase reporter revealed that the behavioural defects were preceded by induction of astrogliosis, a finding consistent with a role for reactive astrocytes in amyotrophic lateral sclerosis pathogenesis. These novel transactive response DNA-binding protein 43 transgenic mice mimic several characteristics of human amyotrophic lateral sclerosis-frontotemporal lobar degeneration and they should provide valuable animal models for testing therapeutic approaches.

• Authors: Vivek Swarup, Daniel Phaneuf, Christine Bareil, Janice Robertson, Guy A Rouleau, Jasna Kriz, Jean-Pierre Julien
• Journal: Brain : a journal of neurology (Brain) Vol. 134 Issue Pt 9 Pg. 2610-26 (Sep 2011) ISSN: 1460-2156 [Electronic] England
• PMID: 21752789 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• DNA-Binding Proteins
• Intermediate Filament Proteins
• Membrane Glycoproteins
• Nerve Tissue Proteins
• Neurofilament Proteins
• Peripherins

Topics

• Amyotrophic Lateral Sclerosis (genetics, pathology, physiopathology)
• Animals
• Axons (ultrastructure)
• Behavior, Animal (physiology)
• Cognition Disorders (pathology, physiopathology)
• DNA-Binding Proteins (genetics, metabolism)
• Disease Models, Animal
• Frontotemporal Lobar Degeneration (genetics, pathology, physiopathology)
• Humans
• Inclusion Bodies (pathology)
• Intermediate Filament Proteins (genetics, metabolism)
• Maze Learning
• Membrane Glycoproteins (genetics, metabolism)
• Mice
• Mice, Inbred C3H
• Mice, Inbred C57BL
• Mice, Transgenic
• Middle Aged
• Nerve Tissue Proteins (genetics, metabolism)
• Neurofilament Proteins (genetics, metabolism)
• Neuropsychological Tests
• Peripherins
• Rotarod Performance Test