Involvement of the Ubiquitin-Proteasome System in the Early Stages of Wallerian Degeneration

Abstract

Local axon degeneration is a common pathological feature of many neurodegenerative diseases and peripheral neuropathies. While it is believed to operate with an apoptosis-independent molecular program, the underlying molecular mechanisms are largely unknown. In this study, we used the degeneration of transected axons, termed "Wallerian degeneration," as a model to examine the possible involvement of the ubiquitin proteasome system (UPS). Inhibiting UPS activity by both pharmacological and genetic means profoundly delays axon degeneration both in vitro and in vivo. In addition, we found that the fragmentation of microtubules is the earliest detectable change in axons undergoing Wallerian degeneration, which among other degenerative events, can be delayed by proteasome inhibitors. Interestingly, similar to transected axons, degeneration of axons from nerve growth factor (NGF)-deprived sympathetic neurons could also be suppressed by proteasome inhibitors. Our findings suggest a possibility that inhibiting UPS activity may serve to retard axon degeneration in pathological conditions.

Endoplasmic reticulum stress-induced cell death mediated by the proteasome

“…[23][24][25][26][27] Additionally, the proteasome has been implicated in the early stages of wallerian degeneration after axotomy. 28 In response to DNA damage, the large Bcl-2 homology domain-only protein Mule/ARF-BP1 was shown to ubiquitylate Mcl-1 -an anti-apoptotic Bcl-2 family member -thereby causing its degradation via the proteasome. 29 Also, the Bcl-2 family members Bcl-2, Mcl-1, and Bfl-1 have been shown to undergo proteasomal degradation when critical serine or threonine residues become dephosphorylated in response to treatment with paclitaxel or TNF.…”

WldS, Nmnats and axon degeneration-progress in the past two decades

“…Initially, there was some controversy regarding whether individual fragments of the Wld S gene (UFD2 or Nmnat1), or the entire chimeric gene, are responsible for the phenotypes (Araki et al, 2004;Wang et al, 2005;Zhai et al, 2006;Conforti et al, 2007). In cultured neurons, we and others found that while inhibiting the ubiquitin proteosome system activity can slow down Wallerian degeneration (Zhai et al, 2003;MacInnis and Campenot, 2005), over-expressing Nmnat1 alone could mimic the protective effects of Wld S (Araki et al, 2004;Wang et al, 2005;Sasaki et al, 2006). Such protective effects could be mimicked by exogenously provided NAD or its biosynthetic precursors such as nicotinamide or nicotinamide riboside (Araki et al, 2004;Wang et al, 2005;Sasaki et al, 2006), suggesting that Wld S /Nmnat1 may act, at least partially, through NAD biosynthesis.…”

“…A possible mechanism is related to the ubiquitin-proteasome system (UPS). It has been reported that the UPS is intrinsically required for both developmental and injury-induced axon degeneration (Zhai et al, 2003;Hoopfer et al, 2006). In cultured neurons, inhibiting the activity of the UPS can slow down Wallerian degeneration (Zhai et al, 2003).…”

“…It has been reported that the UPS is intrinsically required for both developmental and injury-induced axon degeneration (Zhai et al, 2003;Hoopfer et al, 2006). In cultured neurons, inhibiting the activity of the UPS can slow down Wallerian degeneration (Zhai et al, 2003). It was reported that VCP binds Npl4 and Ufd2 to target proteins for proteasomal degradation, or bind Ufd1 and Plap to release refolded proteins into the cytoplasm (Halawani and Latterich, 2006).…”

Intergenomic consensus in multifactorial inheritance loci: the case of multiple sclerosis

“…27 The ubiquitin-proteasome system has been shown to play an important role in axon degeneration. 28 PSMC5 and PSMD12, subunits of the proteasome (the latter is a regulatory one) and NM_022739, an ubiquitination regulatory factor, arise therefore as good candidates to mediate in that process. The expression of the ICAM2 receptor is enhanced in early brain lesions in MS, 29 which could be implicating ICAM2 as a candidate gene, analogously to ICAM1.…”