Rethinking ALS: the FUS about TDP-43

Abstract

Mutations in TDP-43, a DNA/RNA-binding protein, cause an inherited form of the neurodegenerative disease amyotrophic lateral sclerosis (ALS). Two recent studies (Kwiatkowski et al., 2009; Vance et al., 2009) now report that mutations in FUS/TLS, another DNA/RNA-binding protein, also trigger premature degeneration of motor neurons. TDP-43 and FUS/TLS have striking structural and functional similarities, implicating alterations in RNA processing as a key event in ALS pathogenesis.

Figure 1. TDP-43 and FUS/TLS mutations in ALS

A. Twenty dominant mutations in TDP-43 have been identified in sporadic (red) and familial (black) ALS patients, with most lying in the C-terminal glycine-rich region. All are missense mutations, except for the truncating mutation TDP-43^Y374X. RRM1 and RRM2: RNA recognition motifs; NLS, nuclear localization signal; (NES), predicted nuclear export signal. Mutation data compiled from (Banks et al., 2008; Corrado et al., 2009; Daoud et al., 2009; Kuhnlein et al., 2008; Lemmens et al., 2009; Rutherford et al., 2008). B. Fifteen mutations have been identified in FUS/TLS in familial ALS cases, with most lying in the last 13 amino acids of the 526 amino acid protein. (Q/G/S/Y rich), an amino terminal region rich in serine, tyrosine, glutamine and glycine residues; (RRM) a RNA recognition motif; (RRG), an arginine and glycine rich region with several RGG repeats; (NES), a predicted nuclear export signal. Data compiled from (Kwiatkowski et al., 2009; Vance et al., 2009). Domains have been defined according to http://www.uniprot.org and http://www.cbs.dtu.dk/services/NetNES.

Figure 2. TDP-43 or FUS/TLS mislocalization in motor neurons of ALS patients

A. TDP-43 immunohistochemistry in spinal cord of a patient carrying mutation TDP-43^G298S. The four motor neurons shown reveal three distinct patterns of TDP-43 accumulation. Image provided by Dr. James Leverenz, Univ. of Washington. B. Schematic of the three different staining patterns within TDP-43 mutant motor neurons in Panel A, including a predominantly nuclear staining; a diffuse granular cytoplasmic staining (possibly preceding inclusion formation) accompanied by nuclear clearing; and a single, focal inclusion. C. FUS/TLS immunohistochemistry in a surviving motor neuron in spinal cord from a patient carrying the mutation FUS/TLS^R521H. Image provided by Drs. Tibor Hortobagyi and Christopher Shaw, Institute of Psychiatry, London.