Abstract
The mammalian target of rapamycin (mTOR) signaling pathway plays a critical role in regulating cell growth, proliferation, and life span. mTOR signaling is a central regulator of autophagy by modulating multiple aspects of the autophagy process, such as initiation, process, and termination through controlling the activity of the unc51-like kinase 1 (ULK1) complex and vacuolar protein sorting 34 (VPS34) complex, and the intracellular distribution of TFEB/TFE3 and proto-lysosome tubule reformation. Parkinson’s disease (PD) is a serious, common neurodegenerative disease characterized by dopaminergic neuron loss in the substantia nigra pars compacta (SNpc) and the accumulation of Lewy bodies. An increasing amount of evidence indicates that mTOR and autophagy are critical for the pathogenesis of PD. In this review, we will summarize recent advances regarding the roles of mTOR and autophagy in PD pathogenesis and treatment. Further characterizing the dysregulation of mTOR pathway and the clinical translation of mTOR modulators in PD may offer exciting new avenues for future drug development.
Highlights
Introduction of mammalian target of rapamycin (mTOR)The target of rapamycin (TOR) was first identified as a target protein of rapamycin, encoded by TOR1 and TOR2 alleles, through screening of rapamycin-resistant mutant yeast [1]
MTOR, which is termed as FKBP12-rapamycin complex-associated protein (FRAP), is a conserved serine/threonine protein kinase, and mTOR belongs to the phosphoinositide-3-kinase (PI3K)-related kinase family of protein kinases [4]. mTOR constitutes the catalytic component of two distinct multiprotein complexes: mTOR complex 1 and mTOR complex 2
Depletion of mTOR results in the induction of autophagy, leading to clearance of A53T α-synuclein [72]. These findings indicate that mTOR activities are increased in Parkinson’s disease (PD) and α-synuclein accumulation may contribute to this process
Summary
The target of rapamycin (TOR) was first identified as a target protein of rapamycin, encoded by TOR1 and TOR2 alleles, through screening of rapamycin-resistant mutant yeast [1]. A key role in regulating cell itgrowth, cell size, stimuli such as insulin level, energy level,isand amino acid level, and involved in protein synthesis, and proliferation mTORC1 a core component in aisseries of signaling networks. It senses different stimuli such as insulin [13,14]. MTOR and is involvedconsists in protein lipid metabolism, metabolism, and autophagy (Rictor), mammalian stress-activated map kinase-interacting protein 1 (mSIN1),companion and proteinof observed mTORC2 consists of mTOR, mLST8, DEPTOR, rapamycin-insensitive with Rictor (Protor) Kinase-interacting protein 1, Rictor, Rapamycin-insensitive companion of mTOR; Protor, Protein observed with Rictor
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