Selective Activation of mTORC1 Signaling Recapitulates Microcephaly, Tuberous Sclerosis, and Neurodegenerative Diseases

Abstract

Mammalian target of rapamycin (mTOR) has been implicated in human neurological diseases such as tuberous sclerosis complex (TSC), neurodegeneration, and autism. However, little is known about when and how mTOR is involved in the pathogenesis of these diseases, due to a lack of animal models that directly increase mTOR activity. Here, we generated transgenic mice expressing a gain-of-function mutant of mTOR in the forebrain in a temporally controlled manner. Selective activation of mTORC1 in embryonic stages induced cortical atrophy caused by prominent apoptosis of neuronal progenitors, associated with upregulation of HIF-1α. In striking contrast, activation of the mTORC1 pathway in adulthood resulted in cortical hypertrophy with fatal epileptic seizures, recapitulating human TSC. Activated mTORC1 in the adult cortex also promoted rapid accumulation of cytoplasmic inclusions and activation of microglial cells, indicative of progressive neurodegeneration. Our findings demonstrate that mTORC1 plays different roles in developmental and adult stages and contributes to human neurological diseases.

Normalizing translation through 4E-BP prevents mTOR-driven cortical mislamination and ameliorates aberrant neuron integration

“…S7 B-D). This result is in agreement with a previous study that also found that S6K1/2 knockdown was not sufficient to block mTORC1-induced neuronal misplacement (6).…”

“…S3). Finally, we examined soma size because increased mTORC1 activity causes cellular hypertrophy (6,(21)(22)(23). As expected, a 2.1-fold increase in soma area was observed in Rheb CA -electroporated cells relative to controls (Fig.…”

“…The high incidence of negative outcomes in individuals with such malformations (2), which are often associated with intractable childhood seizures, underscores the need to better understand the molecular etiology of these developmental lesions. Animal models have demonstrated the causative effect of increased mTORC1 signaling on mislamination (3)(4)(5)(6)(7). The pharmacological mTORC1 blocker rapamycin has also been shown to reverse some of the developmental abnormalities and associated seizure activity in several of these mouse models (5,6,(8)(9)(10), further emphasizing the importance of mTORC1 in the disease pathogenesis.…”

Neurotensin stimulates sortilin and mTOR in human microglia inhibitable by methoxyluteolin, a potential therapeutic target for autism

“…These findings provide evidence why some patients with ASD who have gene mutations in one negative regulatory protein of mTOR, the phosphatase and tensin homolog (63,64), develop inflammation of the brain that is linked to ASD pathogenesis (65,66).…”

The emerging roles of protein homeostasis‐governing pathways in Alzheimer's disease

“…Transgenic overexpression of mTOR in murine brains culminates in cortical atrophy and neurodegeneration (Kassai, Sugaya, Noda, Nakao, & Maeda, 2014), while conditional knockout of Tsc1 (TSC complex subunit 1), an mTOR inhibitor, has also successfully induced the neurodegenerative abnormalities in mouse brains, a phenocopy of AD pathophysiology (Carson, Nielen, Winzenburger, & Ess, 2012) (Table 2). At present, activation of mTOR has been recognized as a major event that causes AD pathogenesis (Yates, Zafar, Hubbard, Nagy, & Durant, 2013).…”