TDP-43: the relationship between protein aggregation and neurodegeneration in amyotrophic lateral sclerosis and frontotemporal lobar degeneration

Abstract

Accumulations of aggregated proteins are a key feature of the pathology of all of the major neurodegenerative diseases. Amyotrophic lateral sclerosis (ALS) was brought into this fold quite recently with the discovery of TDP-43 (TAR DNA binding protein, 43 kDa) inclusions in nearly all ALS cases. In part this discovery was fueled by the recognition of the clinical overlap between ALS and frontotemporal lobar degeneration, where ubiquitinated TDP-43 inclusions were first identified. Later the identification of TDP-43 mutations in rare familial forms of ALS confirmed that altered TDP-43 function can be a primary cause of the disease. However, the simple concept that TDP-43 is an aggregation-prone protein that forms toxic inclusions capable of promoting neurodegeneration has not been upheld by initial investigations. This review discusses observations from human pathology, cell culture and animal model systems, to highlight our somewhat murky understanding of the relationship between TDP-43 aggregation and neurodegeneration.

Figure 1. Pathology, biochemistry and domain structure of TDP-43

A) Photomicrograph of TDP-43 immunostaining of a spinal motor neuron in a case of ALS. Courtesy of Dr. Nigel Cairns. B) Schematic diagram of TDP-43 pathology in neurodegeneration. Normally, TDP-43 is present as full length protein in the nucleus. In neurodegenerative diseases, inclusions (commonly skein-like as in A) appear predominantly in the cytosol, with loss of nuclear staining. C) Schematic western blot of detergent insoluble material showing full length and C-terminal fragments of TDP-43, with abnormal phosphorylation. 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 domain. The putative location of the prion related domain is shown (see text for details).