Neurotrophic factors regulate RGC survival and

Neurotrophic factors regulate RGC survival and neurite growth through both common and distinct downstream signaling pathways (Goldberg et al., 2002). For example, MAPK/ERK and PI3K/AKT signaling pathways are involved in BDNF induced neuronal survival and axonal growth (Nakazawa et al., 2002) whereas CNTF elicits its biological actions through JAK/STAT3, PI3K/AKT, and MAPK/ERK signaling pathways (Goldberg et al., 2002, Ip and Yancopoulos, 1996, Peterson et al., 2000, Dolcet et al., 2001, Kaur et al., 2002). The mechanisms how mAKAPα scaffolding contributes to neurotrophic dependent- and/or independent-RGC survival and axon growth will need to be elucidated in future studies. As indicated above, mAKAPα can target both ERK5 and PKA to the neuronal nuclear envelope (Michel et al., 2005). MAPK signaling is critical for the survival effects of neurotrophic factors in RGCs (Goldberg et al., 2002). In RGCs and other neurons, ERK5 mediates neurotrophin-dependent (including BDNF), retrograde pro-survival signaling that is initiated in the axon (Watson et al., 2001, Pazyra-Murphy et al., 2009, Wang et al., 2006, van Oterendorp et al., 2014). cAMP also potentiates CNS neuronal survival and axon growth in response to neurotrophic factors (Goldberg et al., 2002). The underlying mechanism for this potentiation remains obscure, but likely involves crosstalk between activity-induced, Ca-dependent signaling pathways and neurotrophic factor-induced MAPK signaling pathways (Steinberg and Brunton, 2001). mAKAPα provides a potential platform for such crosstalk, since it binds machinery critical to both cAMP and MAPK signaling (Dodge-Kafka et al., 2005). Both ERK5 and its upstream activator, MEK5, indirectly bind mAKAP through the phosphodiesterase PDE4D3 (Dodge-Kafka et al., 2005). Interestingly, ERK5 GS-9620 of PDE4D3 has been shown to inhibit local cAMP degradation, increasing PKA activity (Dodge-Kafka and Kapiloff, 2006). Thus, at mAKAPα signalosomes cAMP and MAPK signaling can synergistically oppose retrograde cell death after axon injury (Fig. 4Q). How different signaling pathways are involved, and balanced in the mAKAPα complex for particular function (neuronal survival and/or neurite growth) under different conditions are of great interest and will need to be further elucidated in future studies. Other mAKAP binding partners have been reported to promote the survival and axon growth of CNS neurons, including for example, the Ca/calmodulin-dependent phosphatase calcineurin and the transcription factor MEF2 (Passariello et al., 2015, Akhtar et al., 2012). The unique mAKAPα N-terminal domain not present in mAKAPβ can directly bind PDK1 (Michel et al., 2005). PDK1 binding to mAKAPα can contribute to the activation of p90 ribosomal S6 kinase (RSK) that promotes neuronal survival in response to neurotrophic factors by both transcription-dependent and -independent mechanisms. For example, by direct phosphorylation RSK inactivates BAD, a pro-apoptotic protein family member, and activates transcription factor cAMP response element-binding protein (CREB) (Bonni et al., 1999).
Author Contributions
Disclosures
Acknowledgments We gratefully acknowledge funding from the NEI (R01-EY022129 to MSK and JLG; P30-EY022589 to UCSD), and an unrestricted grant from Research to Prevent Blindness, Inc.
Introduction Age-related myelin breakdown occurs during normal aging and in major neurodegenerative diseases including Alzheimer\'s (Bartzokis, 2004; DeCarli et al., 1995; Erten-Lyons et al., 2013; Ge et al., 2002; Lu et al., 2013; Lebel et al., 2012; Zhang et al., 2007; Tang et al., 1997). White matter degeneration in Alzheimer\'s disease (AD) worsens with progression of disease and is predictive of cognitive decline (Bartzokis, 2004; DeCarli et al., 1995; Erten-Lyons et al., 2013; Ge et al., 2002; Lu et al., 2013; Lebel et al., 2012; Zhang et al., 2007; Tang et al., 1997). Brain regions that myelinate late in brain development and which are populated by small, thinly myelinated are most vulnerable to breakdown and degeneration in AD. Late-myelinating regions include cortical association areas such as fronto-parietal tracts, the genu of the corpus callosum (CC), the uncinate fasiculus, and the superior longitudinal fasiculus (Brickman et al., 2012; Marner et al., 2003). Further, the afferent targets of these fiber systems, which include the hippocampus and subiculum, also show white matter (WM) hyperintensities (Di Paola et al., 2010; Brickman et al., 2012; Marner et al., 2003). Many of these vulnerable fiber tracts, such as the superior longitudinal fasiculus, the CC, internal capsule, corona radiata, and parahippocampal WM also have a high degree of heritability (Sprooten et al., 2014; Jahanshad et al., 2013). Myelin breakdown manifests earlier in apolipoprotein ε4 (APO-ε4) carriers, a major genetic risk factor for AD (Bartzokis et al., 2006). Regions most vulnerable to WM degeneration map onto regions preferentially affected in the pathological trajectory of AD (Bartzokis, 2004), suggesting a possible link between mechanistic pathways affected early in AD progression, and late stage WM degeneration and cognitive deficits.