Directional proteasome transport in neurons requires association of the proteasome adaptor protein Ecm29 with microtubule-associated motor proteins kinesin family member 5B (KIF5B) and/or dynein (Gorbea et al., 2004, 2010; Hsu et al., 2015; Otero et al., 2014). a change that positively correlates with a delay in the GABAergic response switch. Phenotypically, Ecm29 KO mice showed increased firing frequency of action potentials at early postnatal ages and were hypersusceptible Acetanilide to chemically induced convulsive seizures. Finally, Ecm29 KO neurons exhibited accelerated AIS developmental positioning, reflecting a perturbed AIS morphological plastic response to hyperexcitability arising from proteasome inhibition, a phenotype rescued by ectopic Ecm29 expression or NKCC1 inhibition. Together, our findings support the idea that neuronal maturation requires regulation of proteasomal distribution controlled by Ecm29. Introduction Local protein turnover reduces cellular stress caused by aberrant protein accumulation, which can promote inadequate responses to external physiological stimuli. The 26S proteasome complex is required for protein degradation, which maintains protein homeostasis to meet multiple requires of functionally impartial cellular compartments, especially in cells with highly polarized morphologies (Terenzio et al., 2017). Mature neurons are polarized into axonal and somatodendritic compartments segregated via a specialized membrane domain name, the axon initial segment (AIS; Grubb et al., 2011; Rasband, 2010). The AIS serves as a protein transport and membrane diffusion checkpoint and relies on the highly organized cytoskeletal adaptor protein ankyrin G (AnkG), which accumulates in the AIS via interactions with other scaffold proteins (Kole and Stuart, 2012; Leterrier, 2018). Whether and how proteasome complexes and AIS structures function together to control neuronal maturation Acetanilide is not known. Prior to AIS formation in newly differentiated hippocampal neurons, a long-range transport mechanism reportedly selectively controls proteasome abundance in nascent axons (Hsu et al., 2015; Otero et al., 2014). Directional proteasome transport in neurons requires association of Rabbit polyclonal to ZNF200 the proteasome adaptor protein Ecm29 with microtubule-associated motor proteins kinesin family Acetanilide member 5B (KIF5B) and/or dynein (Gorbea et al., 2004, 2010; Hsu et al., 2015; Otero et al., 2014). As a major proteasome adaptor/scaffold and chaperone (Kajava et al., 2004; Leggett et al., 2002; Wani et al., 2016), Ecm29 confers functions in both proteasome particle assembly/disassembly and proteasome mobility/localization via direct proteasome interactions under different cell contexts (De La Mota-Peynado et al., 2013; Lee et al., 2011; Lehmann et al., 2010; Panasenko and Collart, 2011; Wang et al., 2017b; Wani et al., 2016). It is likely that Ecm29-associated proteasomal activity and distribution change as neurons mature morphologically and functionally. As such, cytoplasmic 26S proteasome particles targeting different subcellular compartments may require diverse Ecm29 associations with different sets of adaptors, depending on local molecular and Acetanilide structural properties (Gorbea et al., 2010; Tai et al., 2010). However, whether and how Ecm29 controls proteasome targeting or retention to newly emerged subcellular structures, such as the AIS membrane or synapses, is unclear. As a structure, the AIS initially appears at the proximal end of a growing axon within the first few postnatal days (P; P1 to P2 for rat cortical neurons in vivo [Galiano et al., 2012]) or in 2C7 d in vitro (DIV; in rat cortical/hippocampal cultures [Yang et al., 2007]) before young neurons undergo several stages of structural remodeling concurrent with emergence of neuronal activity (Yang et al., 2007). Precisely when the AIS is usually initially optimized to modulate synaptic input and output in afferent rodent cells remains unclear. Notably, apart from the AIS serving as the initiation site for action potentials (APs) in mature neurons, AIS formation is closely followed by an excitation-to-inhibition transition in the case of -aminobutyric acid (GABA)-ergic responses. This activity represents a critical perinatal windows (during the first or second postnatal week in rodent pyramidal hippocampal neurons; Banke and McBain, 2006; Ben-Ari et al., 1989; Khazipov et al., 2004), setting the stage for lifelong excitatory/inhibitory balance and local circuit homeostasis (Amin et al., 2017; Ben-Ari, 2002; Cellot and Cherubini, 2014; Ganguly et al., 2001). Given that AIS damage due to disease or injury leads to nervous system dysfunction (Buffington and Rasband, 2011; Schafer et al., 2009), AIS-associated functions and the GABA polarity switch may functionally interact. To understand physiological and functional interactions between proteasome complexes and the AIS at early stages of neuronal maturation, we investigated mechanisms regulating proteasome.
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