Amyotrophic lateral sclerosis (ALS) is a fatal adult-onset neurodegenerative disease characterized by loss of motor neurons that leads to the progressive atrophy of skeletal muscles. Of all ALS cases, ~10% are familial and ~90% are sporadic. Although the extensive studies in familial ALS previously identified ALS-causing genes such as superoxide dismutase 1 (SOD1), TAR DNA-binding protein (TARDBP, also known as TDP-43), fused in sarcoma (FUS), and optineurin (OPTN), the exact pathogenic mechanism underlying motor neuron degeneration in ALS remains unclear. In most ALS motor neurons, mislocalization and accumulation of ubiquitinated inclusions containing mutated gene products is a common feature, indicating that a failure to eliminate detrimental proteins is linked to pathogenesis of ALS.
Recently, we created motor neuron-specific conditional knockout mice of Rpt3 (Rpt3-CKO mice), a subunit of 19S particle that form 26S proteasome (Tashiro et al., J.Biol.Chem., 2012). Rpt3-CKO mice displayed mislocalization and accumulation of ALS-linked proteins such as TDP-43 and FUS in motor neurons accompanied by progressive motor neuron loss and locomotor dysfunction. These findings indicate that the proteasome dysfunction is closely related to pathogenesis of ALS.
We, then, tried to assess the effects of ubiquitin-proteasome system (UPS) dysfunction on pathogenesis of ALS, by comparing microarray profiles of motor neurons between control and Rpt3-CKO mice. Here, we conducted microarray analysis using motor neurons collected by laser microdissection, and detected candidate genes.