Rethinking ALS: the FUS about TDP-43

Department of Cellular and Molecular Medicine, University of California San Diego, Ludwig Institute for Cancer Research, La Jolla, CA 92093-0670, USA.
Cell (Impact Factor: 32.24). 04/2009; 136(6):1001-4. DOI: 10.1016/j.cell.2009.03.006
Source: PubMed


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.

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    • "The occurrence of ALS and frontotemporal lobar degeneration with ubiquitin inclusions (FTLD-U) in some families, and the discovery that the transactive response DNA-binding protein 43 (TDP-43) is present in the cytoplasmic aggregates of both diseases, provided the first set of clues that the two diseases may share a common underlying mechanism [29]. TDP-43 is a DNA/RNA binding protein that contains an N-terminal domain, two RNA-recognition motifs, and a glycine-rich C-terminal domain thought to be important in the mediation of protein-protein interactions [30, 31]. It serves a plethora of cellular functions but its implication in neurodegenerative diseases was primarily substantiated by the discovery of dominantly inherited missense mutations in TDP-43, which are present in patients with familial form ALS [21, 32–36]. "
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    • "The progression of ALS is rapid, with most patients surviving only a few years following diagnosis; the only approved treatment for ALS, Rilutek (Riluzole), shows only marginal effect on disease progression. Studies over the last 20 years have uncovered ALS-causing mutations in several genes such as SOD1, TDP-43 (TARDBP), FUS (TLS) and C9ORF72 (Chen et al., 2004; DeJesus-Hernandez et al., 2011; Greenway et al., 2006; Kabashi et al., 2011; Kiernan et al., 2011; Kwiatkowski et al., 2009; Lagier-Tourenne and Cleveland, 2009; Renton et al., 2011; Rosen et al., 1993; Sreedharan et al., 2008; Vance et al., 2009). "
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    • "Mutations in TDP-43 have been identified in familial and sporadic cases of ALS and FTLD-TDP, mainly in the C-terminal glycine-rich region, including the M337V mutation caused by an alteration of an adenine (A) to guanine (G) at position 1009 of TARDBP cDNA [3], [11], [12], [13], [14], [15], [16]. In a recent study using isogenic lines, mutant forms of TDP-43 were reported to be more stable than wild-type which was degraded two to four times faster than mutant TDP-43 [17]. "
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