, 2011). Ubiquilin-1 interacts with TDP-43 and overexpression of ubiquilin-1 can recruit TDP-43 into cytoplasmic Selleck NVP-BGJ398 aggregates that colocalize with autophagosomes

in cultured cells (Kim et al., 2009). Finally, p62/sequestosome-1 is misaccumulated in both ALS and FTD (Seelaar et al., 2007) along with TDP-43 (Tanji et al., 2012), while increased expression of it reduces TDP-43 aggregates in cultured cells (Brady et al., 2011). Taken together, these findings indicate that ALS/FTD-linked mutations in genes that are involved in protein homeostasis can directly contribute to TDP-43 proteinopathy. Except for ubquilin-2 mutations (Deng et al., 2011 and Williams et al., 2012), inclusion of FUS/TLS has not been reported in response to mutations or disruption of ALS-linked genes involved in the protein homeostasis pathways. However, as described above, one class of ALS-linked mutations disrupts nuclear localization signals, producing higher cytosolic accumulation of FUS/TLS (Dormann et al., 2010 and Bosco et al., 2010a). This relocalization of FUS/TLS may be a primary cause for initiating FUS/TLS proteinopathies. TDP-43 affects levels of RNAs selleck screening library that encode proteins involved in protein homeostasis, including

CHMP2B, FIG4, OPTN, VAPB, and VCP ( Polymenidou et al., 2011). Additionally, TDP-43 has been shown to bind the pre-mRNA encoding the autophagy-related 7 (Atg7) protein essential for autophagy, with reduction of TDP-43 downregulating Atg7, thereby impairing autophagy ( Bose et al., 2011). It is worth mentioning that mice lacking Atg5 and Atg7 in the nervous system exhibit neurodegeneration ( Hara and et al., 2006 and Komatsu et al., 2006), strongly suggesting—not unexpectedly—that autophagy is essential for normal neuronal function. Altogether, these results suggest an intricate regulatory network in which TDP-43 can affect the expression of the very gene(s) that participate in TDP-43 clearance, providing an additional mechanism of regulating TDP-43 abundance (the other being the autoregulation of TDP-43 by binding to its own mRNA), while TDP-43 also

indirectly affects global protein clearance pathways by regulating the expression of key components in autophagy. Similarly, FUS/TLS binds to the mRNAs encoding optineurin (Lagier-Tourenne et al., 2012 and Colombrita et al., 2012), ubiquilin-2 (Lagier-Tourenne et al., 2012 and Hoell et al., 2011), VAPB (Lagier-Tourenne et al., 2012 and Hoell et al., 2011), and VCP (Lagier-Tourenne et al., 2012, Colombrita et al., 2012 and Hoell et al., 2011), although reduction of FUS/TLS in the mouse CNS does not significantly alter their expression levels (Lagier-Tourenne et al., 2012). In a motoneuron-like cell line, FUS/TLS has been argued to be preferentially bound to cytoplasmic mRNAs that are involved in the ubiquitin-proteasome pathway, in particular the cullin-RING E3 ubiquitin ligases (Colombrita et al., 2012).