TDP-43-based animal models of neurodegeneration: new insights into ALS pathology and pathophysiology

Abstract

The clinical and pathological overlap between amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD) suggests these diseases share common underlying mechanisms, a suggestion underscored by the discovery that TDP-43 inclusions are a key pathologic feature in both ALS and FTLD. This finding, combined with the identification of TDP-43 mutations in ALS, directly implicates this DNA/RNA binding protein in disease pathogenesis in ALS and FTLD. However, many key questions remain, including what is the normal function of TDP-43, and whether disease-associated mutations produce toxicity in the nucleus, cytoplasm or both. Furthermore, although pathologic TDP-43 inclusions are clearly associated with many forms of neurodegeneration, whether TDP-43 aggregation is a key step in the pathogenesis in ALS, FTLD and other disorders remains to be proven. This review will compare the features of numerous recently developed animal models of TDP-43-related neurodegeneration, and discuss how they contribute to our understanding of the pathogenesis of human ALS and FTLD.

Fig. 1

Pathology and genetics of TDP-43 in ALS and FTLD. a Skein-like TDP-43 inclusions in the cytoplasm of a spinal motor neuron in a case of ALS, with loss of normal nuclear staining. Photomicrograph courtesy of Dr. Nigel Cairns. b Schematic diagram of TDP-43 pathology in affected neurons in ALS and FTLD. Normally, TDP-43 is present as full-length protein in the nucleus. In cases of ALS and FTLD, inclusions of the protein appear predominantly in the cytosol, with loss of nuclear staining. This correlates with the presence of cleaved and phosphorylated C-terminal fragments observed on Western blotting (c). d Line diagram of TDP-43 showing the RNA binding motifs (RRM1 and RRM2), nuclear localization signal (NLS), nuclear export signal (NES), and location of the ALS/FTLD associated mutations (arrowheads) in the C-terminal prion-related domain.

Fig. 2

Schematic plot of the relationship between expression levels of TDP-43 and SOD1 and the development of features of ALS (phenotype). Low levels of TDP-43 produce little or no detectable phenotype. At a threshold of expression around 3-fold above endogenous levels, mice begin to develop features of ALS and FTLD pathology. Although the ALS-associated mutants appear to be more toxic than the wild-type protein, this still needs to be carefully examined given the mix of different promoters used to make existing mouse lines. In the case of SOD1, much higher levels are required to produce toxicity (∼20 fold); however, the difference in toxicity between mutant and wild-type SOD1 forms is much more pronounced.