Hyperactivation of mTORC1 disrupts cellular homeostasis in cerebellar Purkinje cells

Abstract

Mammalian target of rapamycin (mTOR) is a central regulator of cellular metabolism. The importance of mTORC1 signaling in neuronal development and functions has been highlighted by its strong relationship with many neurological and neuropsychiatric diseases. Previous studies demonstrated that hyperactivation of mTORC1 in forebrain recapitulates tuberous sclerosis and neurodegeneration. In the mouse cerebellum, Purkinje cell-specific knockout of Tsc1/2 has been implicated in autistic-like behaviors. However, since TSC1/2 activity does not always correlate with clinical manifestations as evident in some cases of tuberous sclerosis, the intriguing possibility is raised that phenotypes observed in Tsc1/2 knockout mice cannot be attributable solely to mTORC1 hyperactivation. Here we generated transgenic mice in which mTORC1 signaling is directly hyperactivated in Purkinje cells. The transgenic mice exhibited impaired synapse elimination of climbing fibers and motor discoordination without affecting social behaviors. Furthermore, mTORC1 hyperactivation induced prominent apoptosis of Purkinje cells, accompanied with dysregulated cellular homeostasis including cell enlargement, increased mitochondrial respiratory activity, and activation of pseudohypoxic response. These findings suggest the different contributions between hyperactivated mTORC1 and Tsc1/2 knockout in social behaviors, and reveal the perturbations of cellular homeostasis by hyperactivated mTORC1 as possible underlying mechanisms of neuronal dysfunctions and death in tuberous sclerosis and neurodegenerative diseases.

Sensitive period for rescuing parvalbumin interneurons connectivity and social behavior deficits caused by TSC1 loss

“…Finally, while rapamycin, a mTORC1 blocker, was effective in rescuing PV cell connectivity and social behavior deficits in PV-Cre ; Tsc1 lox/+ mice, we cannot exclude that Tsc1 deletion might have additional effects independent of mTORC1 signaling, since mice carrying hyperactive mTORC1 in Purkinje cells were recently reported to display different behavioral alterations compared to Purkinje-cell specific Tsc1-lacking mice 65 . A better understanding of the complexity of mTORC1 signaling network regulation, feedback and compensatory loops, may lead to the discovery of new molecular drug targets.…”

SETX (senataxin), the helicase mutated in AOA2 and ALS4, functions in autophagy regulation

“…These include gait ataxia, cerebellar degeneration and male sterility, but a normal lifespan [78,79]. Additionally, expression of a hyperactive form of MTOR in the mouse cerebellum also leads to cerebellar atrophy and shows increased mitochondrial biogenesis, confirming the importance of MTORC1 signaling in Purkinje cell survival [80]. Notably, these mice also exhibited ataxic gait.…”

Transcriptomic Changes Associated with Loss of Cell Viability Induced by Oxysterol Treatment of a Retinal Photoreceptor-Derived Cell Line: An In Vitro Model of Smith–Lemli–Opitz Syndrome

“…Because the mTORC 1/2 signaling pathways have been shown to impact cell survival, including playing a role in neurodegeneration [ 73 , 74 , 75 ], we next evaluated enrichment terms relevant for these in our gene array results ( Figure 12 ). The set of up-regulated, but not down-regulated, oxysterol-induced DEGs exhibited a statistically significant correlation for the GO term “Tor signaling,” which includes genes for both mTorc1 and mTorc2 ( Figure 12 A).…”