This process is thought to be at play in ALS (Kanekura et al., 2009). Mutant SOD1 has been found to Pexidartinib mouse accumulate in the ER and to inhibit derlin-1, the protein that transports proteins destined to be degraded from the ER to the cytosol (Nishitoh et al., 2008). Furthermore, a decrease in proteasome activity has been found in mutant SOD1-overexpressing cells and tissue (Urushitani et al., 2002; Kabashi et al., 2004, 2008a; Cheroni et al., 2009). Mutant SOD1 thus induces ER stress, and may overload the UPR response and the proteasome system. Upregulation of ER stress molecules has been correlated with the vulnerability of motor neurons in mutant SOD1 mice

(Saxena et al., 2009). Overexpression of heat-shock proteins (HSPs) in vitro rescues the cell from mutant SOD1-induced

toxicity (Patel et al., 2005). Disappointingly, neither HSP27 nor HSP70 overexpression in vivo affected motor neuron degeneration in mutant SOD1 mice (Liu et al., 2005; Krishnan et al., 2008). It is obvious that overexpressing one component of this sophisticated system may be insufficient. The misfolded mutant SOD1 that escapes the cellular degradation system may interact with aberrant binding partners (such as mitochondrial membranes or chromogranins; see above) or form oligomers which then may proceed to the formation of higher molecular species and finally aggregate into intracellular Afatinib in vitro inclusions (Johnston et al., 2000; Rakhit et al., 2002; Ezzi et al., 2007; Teilum et al., 2009). It is thought but not certain that this process is toxic for the neuron. Which stage of formation of inclusions is responsible for toxicity is uncertain, as is the question whether wildtype SOD1, which can form heterodimers with mutant SOD1 or can be recruited to coaggregate with it, contributes to this toxicity (Bruijn et al., 1998; Jaarsma et al., 2000; Fukada et al., 2001; Lemmens et al., 2007;

Wang et al., 2009b). Aggregates may deplete the cell of essential constituents by coaggregation, or may physically disturb cellular processes such axonal transport (axonal strangulation; De Vos et al., 2007). However, just like for many other neurodegenerative diseases, it remains Idoxuridine unknown whether aggregation of mutant protein is a hazardous or a protective phenomenon. It may well be that the first stages of the process (oligomerisation) are toxic (Johnston et al., 2000; Wang et al., 2002) while the aggregates themselves are essentially inert. The convergence of damage in non-neuronal cells surrounding motor neurons has a larger impact on motor neuron survival then initially anticipated (Ilieva et al., 2009). Several types of non-neuronal cells, such as microglia and astrocytes, are activated in the course of the neurodegenerative process in ALS (Hall et al., 1998).