Indeed, reducing SOD1 expression has been reported to slow disease progression of transgenic mice and rats expressing human mutant SOD1 Olaparib nmr (Ralph et al., 2005, Raoul et al., 2005 and Smith et al., 2006). A further glimmer of hope has emerged from a successful phase I safety trial using antisense oligonucleotides against SOD1 in patients carrying mutant SOD1 (Miller et al., 2013). A similar strategy targeting the potentially toxic RNA species or RAN translation of it can be envisioned for the more frequent instances of disease from hexanucleotide expansion in C9ORF72. Several lines of evidence indicate that broad defects in protein homeostasis
may contribute to ALS pathogenesis: (1) all ALS patients have one of the following protein inclusions in affected motor neurons: TDP-43, FUS/TLS, or SOD1; (2) ALS-linked mutations are identified in several selleck chemicals llc genes involved in ER stress, autophagy, and the ubiquitin-proteasome pathway; (3) ALS-linked mutations in ubiquilin-2, CHMP2B, and VCP can lead to TDP-43 aggregation; (4) dysfunctions in ERAD and autophagy are observed in mouse models expressing mutant SOD1; and (5) autophagy appears to be activated and upregulated in motor neurons of sporadic ALS patients. It is not clear how a decline in general protein
degradation machinery might cause aggregation of specific proteins in different neurodegenerative diseases. However, it is conceivable that increasing (or delaying age-dependent decline in) proteostasis could, in principle, prevent or slow down the formation of protein inclusions—or 17-DMAG (Alvespimycin) HCl at least accumulation of some or all of the toxic protein species. Initial hints that this approach could be beneficial came from report of modest delay in disease progression following treatment of a very small number of mice with arimoclomol, an inducer of heat shock proteins HSP70 and HSP90 (Kieran et al., 2004). Phase 2/3 clinical trials are currently underway for this approach. Dampening the UPR by deleting a downstream
X-box-binding protein (XBP-1) was reported to provide a modest survival benefit (∼20 days) to a small cohort (n = 7) of SOD1G86R mice, but the apparent benefit was disappointingly found only in female mice (Hetz et al., 2009). Finally, pharmacological activation of autophagy was reported in another small cohort of mice (n = 10 per drug treatment) to improve cognitive and motor phenotype in male mice overexpressing wild-type TDP-43 (Wang et al., 2012). Independent replications of the above experiments with larger cohorts that are powered to provide statistical significance—and extended to multiple ALS/FTD mouse models—are now needed to validate the therapeutic potential of these approaches.