Akt Suppresses Retrograde Degeneration of Dopaminergic Axons by Inhibition of Macroautophagy

Abstract

Axon degeneration is a hallmark of neurodegenerative diseases, including Alzheimer's disease and Parkinson's disease. Such degeneration is not a passive event but rather an active process mediated by mechanisms that are distinct from the canonical pathways of programmed cell death that mediate destruction of the cell soma. Little is known of the diverse mechanisms involved, particularly those of retrograde axon degeneration. We have previously observed in living animal models of degeneration in the nigrostriatal projection that a constitutively active form of the kinase, myristoylated Akt (Myr-Akt), demonstrates an ability to suppress programmed cell death and preserve the soma of dopamine neurons. Here, we show in both neurotoxin and physical injury (axotomy) models that Myr-Akt is also able to preserve dopaminergic axons due to suppression of acute retrograde axon degeneration. This cellular phenotype is associated with increased mammalian target of rapamycin (mTor) activity and can be recapitulated by a constitutively active form of the small GTPase Rheb, an upstream activator of mTor. Axon degeneration in these models is accompanied by the occurrence of macroautophagy, which is suppressed by Myr-Akt. Conditional deletion of the essential autophagy mediator Atg7 in adult mice also achieves striking axon protection in these acute models of retrograde degeneration. The protection afforded by both Myr-Akt and Atg7 deletion is robust and lasting, because it is still observed as protection of both axons and dopaminergic striatal innervation weeks after injury. We conclude that acute retrograde axon degeneration is regulated by Akt/Rheb/mTor signaling pathways.

AAV Transduction of Dopamine Neurons With Constitutively Active Rheb Protects From Neurodegeneration and Mediates Axon Regrowth

“…Indeed, we have reported that both Myr-Akt and hRheb(S16H) are capable of providing such protection acutely following neurotoxin injection. 18 Alternatively, axon degeneration may ultimately have taken place over the course of the four postlesion weeks, but following this axon loss, new axon growth from remaining neurons may have been induced. Such a possibility is in keeping with our proposal that hRheb induces sprouting in normal adult dopamine neurons.…”

“…[13][14][15][16] We have demonstrated that transduction of dopamine neurons of the substantia nigra (SN) with a constitutively active form of Akt, myristoylated-Akt (Myr-Akt), induces an array of neurotrophic effects in these neurons, including hypertrophy, increased expression of neurotransmitter synthetic enzymes, axon sprouting, and resistance to neurotoxin-induced cell death 17 and axon degeneration. 18 While these observations provide a compelling proof-of-concept, that an adeno-associated virus (AAV) vector in current clinical use 19 can be used to mediate neurotrophic effects by cellular transduction, further investigation with a specific focus on the pathways that mediate clinically important phenotypic effects is needed.…”

Programmed Cell Death in Parkinson's Disease

“…Cellular phenotypes of necrosis, apoptosis, and autophagy can indeed coexist in the same cell (Lemasters et al 2002). In addition, cell soma and axon degeneration may be governed by different pathways (Bilsland et al 2002;Raff et al 2002;Ries et al 2008;Cheng et al 2011).…”

Rheb in neuronal degeneration, regeneration, and connectivity

“…Even though inhibition of autophagy leads to cell death and neurodegeneration (Rubinsztein, 2006;Sarkar and Rubinsztein, 2008;Wang et al, 2009), excessive autophagy by inhibition of Rheb-mTORC1 pathway can result in axon degeneration following acute injury (Cheng et al, 2011b). Increased Akt-mTORC1 dependent macroautophagy induces retrograde axon degeneration in dopaminergic neurons after acute chemotoxic injury (Cheng et al, 2011b;Wang et al, 2012).…”

“…Increased Akt-mTORC1 dependent macroautophagy induces retrograde axon degeneration in dopaminergic neurons after acute chemotoxic injury (Cheng et al, 2011b;Wang et al, 2012). Therefore, the ability of Akt or Rheb to protect axons from retrograde degeneration is likely to be due to its ability to suppress autophagy through mTORC1 signaling (Cheng et al, 2011b).…”