Lakhasly

Parkinson’s disease (PD) is one of the most common neurodegenerative diseases in the world, characterized mainly by dopaminergic neuron loss in the substantia nigra pars compacta (SNpc) and the accumulation of α-synuclein-containing inclusions, named Lewy bodies. Genetic mutations are the leading cause of the disease, but it can also be caused by aging or dopaminergic neuron-specific toxins, such as 6-hydroxydopamine (6-OHDA), 1-methyl-4-phenyl-1,2,3,6 tetrahydropyridine (MPTP), and rotenone [65]. Among these toxins, MPTP has been widely used for developing the PD animal model [66]. Actually, MPTP itself is nontoxic and can penetrate the blood–brain barrier. While in the brain, it can be oxidized to MPP+, which is toxic to dopaminergic neurons [67]. Thus, MPTP is usually used for animal models of PD, and MPP+ is used for cell models of PD. As mTOR signaling is a central hub of signaling networks in cells, it has been widely explored and has been found to have a complex relationship with PD. Both activation and inactivation of mTOR signaling are involved in the different stages of PD.
α-synuclein accumulation is a hallmark of PD, which has been implicated in the pathogenesis of sporadic and familial PD [68,69]. mTOR protein expression levels were increased in the temporal cortex of patients displaying α-synuclein accumulation [70]. Additionally, upon overexpression of α-synuclein, it can inhibit autophagy possibly through inducing mTOR activity and mimic the symptoms of PD [71]. Conversely, rapamycin, an inhibitor of mTOR, can restore the increased mTOR activity caused by α-synuclein overexpression [71]. What is more, A53T α-synuclein, a common mutation of α-synuclein in PD, upregulates mTOR/P70S6K signaling and impairs autophagy, contributing to the aggregation of toxic A53T α-synuclein [72]. On the other hand, 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 PD and α-synuclein accumulation may contribute to this process.
RTP801/REDD1 is a stress-related protein, whose expression is markedly elevated in neurons of the SNpc in PD patients compared to control patients [73]. RTP801 interacts with TSC2, inhibiting activation of mTOR and thus leading to neuron cell death; this process may account for the neuron loss in the SNpc of PD patients [74,75]. An increase in RTP801 expression is also observed in cellular models of PD (6-OHDA, MPP+ or rotenone) and in animal models of PD. In both cases, the increased RTP801 expression is accompanied by decreased mTOR activity [73].
It is well known that mTOR signaling is of great importance in cell proliferation and survival. The phosphorylation of Akt, the upstream kinase of mTOR, is decreased in the MPP+-induced cellular model of PD, attenuating the activation of mTOR [76]. In addition, AMPK is a negative regulator of mTOR, which is activated in different cellular models of PD [77]. Thus, in PD models induced by toxins, both increased Akt and AMPK could negatively regulate the activity of mTOR, leading to the impairment of downstream 4EBP1 and P70S6K-related protein synthesis. This protein synthesis is essential for cell long-term survival. Furthermore, neuronal cell death induced by PD toxins can be partially restored via overexpression of functional mTOR [77].