Original Article

Citation: Cell Death and Disease (2016) 7, e2279; doi:10.1038/cddis.2016.182
Published online 30 June 2016

TSC but not PTEN loss in starving cones of retinitis pigmentosa mice leads to an autophagy defect and mTORC1 dissociation from the lysosome

A Venkatesh1, S Ma1 and C Punzo1,2

  1. 1Department of Ophthalmology and Gene Therapy Center, University of Massachusetts Medical School, Worcester, MA 01605, USA
  2. 2Department of Neurobiology, University of Massachusetts Medical School, 386 Plantation Street, Worcester, MA 01605, USA

Correspondence: C Punzo, Department of Ophthalmology and Gene Therapy Center, University of Massachusetts Medical School, 368 Plantation Street, Worcester, MA 01605, USA. Tel/Fax: +1 508 856 8038; E-mail: Claudio.Punzo@umassmed.edu

Received 15 April 2016; Revised 13 May 2016; Accepted 31 May 2016

Edited A Verkhratsky



Understanding the mechanisms that contribute to secondary cone photoreceptor loss in retinitis pigmentosa (RP) is critical to devise strategies to prolong vision in this neurodegenerative disease. We previously showed that constitutive activation of the mammalian target of rapamycin complex 1 (mTORC1), by loss of its negative regulator the tuberous sclerosis complex protein 1 (Tsc1; also known as Hamartin), was sufficient to promote robust survival of nutrient-stressed cones in two mouse models of RP by improving glucose uptake and utilization. However, while cone protection remained initially stable for several weeks, eventually cone loss resumed. Here we show that loss of Tsc1 in the cones of RP mice causes a defect in autophagy, leading to the accumulation of ubiquitinated aggregates. We demonstrate that this defect was not due to an inhibition of autophagy initiation, but due to an accumulation of autolysosomes, suggesting a defect in the end-stage of the process causing an amino-acid shortage in cones, thereby hampering long-term cone survival. Because cells with TSC loss fail to completely inhibit mTORC1 and properly activate autophagy in the absence of amino acids, we sporadically administered the mTORC1 inhibitor rapamycin, which was sufficient to correct the defects seen in cones, further enhancing the efficiency of cone survival mediated by Tsc1 loss. Concordantly, activation of mTORC1 by loss of the phosphatase and tensin homolog (Pten) did not affect autophagy and amino-acid metabolism, leading to a more sustained long-term protection of cones. As loss of Pten, which in cones results in less robust mTORC1 activation when compared with loss of Tsc1, still affords long-term cone survival, therapeutic interventions with mTORC1 activators or gene therapy with selected mTORC1 targets that improve glucose metabolism are potential strategies to delay vision loss in patients with RP.


4EBP1, eukaryotic translational initiation factor 4E-binding protein; ALFY, autophagy-linked FYVE protein; AMPK, adenosine monophosphate-activated protein kinase; ATG12, autophagy gene 12; ERG, electroretinogram; FOXO3A, forkhead box protein O3; LAMP, lysosomal-associated membrane protein; LC3, microtubule-associated protein-light chain 3; mTORC, mammalian target of rapamycin complex; Pde6β, phosphodiesterase-6-β; PNA, peanut agglutinin lectin; PTEN, phosphatase and tensin homolog; rAAV, recombinant adeno-associated virus; Raptor, regulatory-associated protein of mTOR; Rictor, rapamycin-insensitive companion of mTOR; rd1, retinal degeneration-1; Rheb, Ras homolog enriched in brain; RP, retinitis Pigmentosa; TFEB, transcription factor EB; TSC, tuberous sclerosis complex; ULK1, Unc-51-like autophagy-activating kinase-1; SW OPSIN, short wave opsin