Ubiquitination in brain development and disease

Ubiquitination drives fundamental aspects of cell biology

Ubiquination 1
Figure 1. Diagram of the cellular biochemistry and biology of ubiquitination. E1 = ubiquitin-activating enzyme; E2 = ubiquitin-conjugating enzyme; DUB = deubiquitinase; Ub = ubiquitin.

Ubiquitination is a major post-translational modification that governs a diverse array of normal biological processes, from developmental events to homeostatic processes. Covalent attachment of ubiquitin to specific substrate proteins results in protein degradation or alteration in protein function/localization. Abnormalities in ubiquitin signaling lead to protein derangements and in certain contexts to human diseases, including tumorigenesis. 

Ubiquitin signaling governs key events in early brain development

Among E3 ligases, the Anaphase-Promoting Complex (APC) is evolutionarily conserved and critical for cell cycle transitions. Via binding of coactivator Cdc20, the APC drives sister chromatid separation at anaphase and mitotic exit through polyubiquitination of cell cycle substrates, which are subsequently degraded by the proteasome. Remarkably, core APC subunits are highly expressed in the mammalian brain, suggesting functions for Cdc20-APC beyond cell division. Recently, I have discovered Cdc20-APC is essential for neuronal morphogenesis in diverse neurons of the brain in culture and in the rodent cerebellar cortex in vivo.

Ubiquination 2
Figure 2. Major mitotic regulator and E3 ligase Anaphase-Promoting Complex is essential for neuronal morphogenesis. A. Lysates from COS cells transfected with indicated plasmids were subjected to immunoblotting. B. Cerebellar granule neurons from P6 rats were transfected with indicated plasmids along with GFP and processed for GFP immunofluorescence. Arrow = dendrite; arrowhead = axon. C. Neurons were transfected with indicated plasmids and processed as in B. Morphometric analysis was performed (total dendrite length + SEM). D. Left: Cdc20 immunofluorescence (red) in neurons revealed a centrosomal localization (arrow). Right: Merge with Hoechst nuclear label.

Figure reprinted with permission from Elsevier. REF: A.H. Kim, S.V. Puram, P.M. Bilimoria, S. Keough, M. Wong, D. Rowitch, and A. Bonni. A centrosomal Cdc20-APC pathway controls dendrite morphogenesis in postmitotic neurons. Cell. 136(2):322-336. 2009.