ALS affects 2 in 100,000 people and has traditionally been considered a disorder in which degeneration of upper and lower motor neurons gives rise to progressive spasticity, muscle wasting, and weakness. However, ALS is increasingly recognized to be a multisystem disorder with impairment
of frontotemporal functions such LDK378 research buy as cognition and behavior in up to 50% of patients (Giordana et al., 2011, Lomen-Hoerth et al., 2003 and Phukan et al., 2007). Similarly, as many as half of FTD patients develop clinical symptoms of motor neuron dysfunction (Lomen-Hoerth et al., 2002). The concept that FTD and ALS represent a clinicopathological spectrum of disease is strongly supported by the recent discovery of the transactive response DNA binding protein with Mr 43 kD (TDP-43) as the pathological protein in the vast majority of ALS cases and in the most common pathological subtype of FTD (Neumann et al., 2006) (now referred to as frontotemporal lobar degeneration with TDP-43 pathology, FTLD-TDP) (Mackenzie et al., 2009). A positive family history is observed in ∼10% of ALS patients (Gros-Louis et al., 2006), while up to 50% of FTD patients report family
members with FTD or related cognitive and behavioral changes (Graff-Radford and Woodruff, 2007), supporting the important contribution of genetic factors to these diseases. The most HIF inhibitor common currently known cause of familial FTLD-TDP involves loss-of-function Ergoloid mutations in the gene for the secreted growth factor progranulin (GRN) ( Baker et al., 2006 and Cruts et al., 2006). Although GRN deficiency has been directly linked to TDP-43 dysfunction and aggregation in a neuronal culture model of disease and in GRN knockout mice, the exact relationship between GRN insufficiency and TDP-43 dysfunction remains unknown ( Ahmed et al., 2010, Guo et al., 2010 and Yin et al., 2010). In familial ALS, ∼15%–20% of patients are found to have
mutations in the Cu/Zn superoxide dismutase gene (SOD1) ( Rosen et al., 1993). Treatments shown to be effective in SOD1 mouse models, however, have generally not been effective in ALS clinical trials, and the absence of TDP-43 pathology in cases with SOD1 mutations suggests that motor neuron degeneration in these cases may result from a different mechanism ( Mackenzie et al., 2007). For these reasons, the recent identification of mutations in TDP-43 (encoded by TARDBP) ( Kabashi et al., 2008 and Sreedharan et al., 2008) and the related RNA-binding protein fused in sarcoma (FUS) ( Kwiatkowski et al., 2009 and Vance et al., 2009) in ∼5% of familial ALS patients has significantly shifted the focus of ALS research and implicated abnormal RNA processing as a critical process in ALS pathogenesis ( Lagier-Tourenne et al., 2010).