TOR-mediated autophagy regulates cell death in Drosophila neurodegenerative disease

Abstract

Target of rapamycin (TOR) signaling is a regulator of cell growth. TOR activity can also enhance cell death, and the TOR inhibitor rapamycin protects cells against proapoptotic stimuli. Autophagy, which can protect against cell death, is negatively regulated by TOR, and disruption of autophagy by mutation of Atg5 or Atg7 can lead to neurodegeneration. However, the implied functional connection between TOR signaling, autophagy, and cell death or degeneration has not been rigorously tested. Using the Drosophila melanogaster visual system, we show in this study that hyperactivation of TOR leads to photoreceptor cell death in an age- and light-dependent manner and that this is because of TOR's ability to suppress autophagy. We also find that genetically inhibiting TOR or inducing autophagy suppresses cell death in Drosophila models of Huntington's disease and phospholipase C (norpA)–mediated retinal degeneration. Thus, our data indicate that TOR induces cell death by suppressing autophagy and provide direct genetic evidence that autophagy alleviates cell death in several common types of neurodegenerative disease.

Autophagy and neurodegeneration

“…Additionally, autophagy also protects against both proapoptotic (95,96) and pro-necrotic (97) insults, which may contribute to its benefits. The protective effect seen from autophagy induction in cell models has been successfully translated into a range of animal models, in Drosophila melanogaster models of both tauopathies (8) and HD (70,98), and also in mammalian models of disease, including HD, spinocerebellar ataxia type III, tauopathy, PD, and even familial prion disease (see Table 1 for studies of autophagy upregulation in mouse models of neurodegeneration). Together these studies demonstrate that autophagy upregulation and promotion of aggregation-prone protein degradation ameliorate neurodegenerative pathology.…”

“…Although the mTOR pathway is involved in a wide range of cellular functions (reviewed in ref. 107), the therapeutic effects of rapamycin in models of neurodegenerative disease are predominantly autophagy mediated (8,98). The limited absorption of rapamycin has driven the development of many so-called rapalogs such as temsirolimus (CCI-779), everolimus (RAD001), and ridaforolimus (AP23573).…”

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).…”

“…mTORC1 consists of mTOR, regulatory-associated protein of mTOR (Raptor); and mammalian lethal with SEC13 protein 8 (mLST8), along with two endogenous inhibitors of the complex, 40 kDa Proline-rich Akt substrate (PRAS40), and DEP domain-containing mTOR-interacting protein (DEPTOR) (Loewith et al, 2002;Hay and Sonenberg, 2004;Long et al, 2005;Yang et al, 2006;Adami et al, 2007). Downstream of activated mTORC1, protein translation is promoted by phosphorylation of 70 kDa ribosomal S6 kinase (S6K) and eukaryotic translation initiation factor 4E-binding protein 1 (4E-BP1) and autophagy is suppressed via Ulk1/Atg13 (Burnett et al, 1998;Hay and Sonenberg, 2004;Ganley et al, 2009;Hosokawa et al, 2009;Jung et al, 2009;Wang et al, 2009;Sciarretta et al, 2012) (see Figure 1). Rapamycin is an immunosuppressant and anticancer agent that binds to a 12-kDa FK506-binding protein (FKBP12) with high affinity.…”

“…Many lines of evidences suggest that intracellular protein degradation pathways such as autophagy and the ubiquitin-proteasome system are deregulated in neurodegenerative diseases and may play key roles in the etiology of these pathologies (Rubinsztein, 2006;Sarkar and Rubinsztein, 2008;Wang et al, 2009;Laplante and Sabatini, 2012;Nixon, 2013). The inhibiton of autophagy in TSC mutant or under Rheb over-expression leads to accumulation of toxic aggregate-prone proteins such as ataxin, Tau, and α-synuclein, which are linked to diseases such as spinocerebral ataxia, AD and PD, respectively (reviewed in Rubinsztein, 2006;Sarkar and Rubinsztein, 2008;Swiech et al, 2008).…”