Cited by 64Parkinson's Disease Mechanisms and TreatmentsNuclear Receptors and SignalingAlzheimer's disease research and treatments

Enhanced mTORC1 signaling and protein synthesis in pathologic α-synuclein cellular and animal models of Parkinson’s disease

Khan, Mohammed Repon, Yin, Xiling, Kang, Sung-Ung, Mitra, Jaba, Wang, Hu, Ryu, Taekyung, Brahmachari, Saurav, Karuppagounder, Senthilkumar S. +11 more·2023·Science Translational Medicine

Abstract

Pathologic α-synuclein plays an important role in the pathogenesis of α-synucleinopathies such as Parkinson’s disease (PD). Disruption of proteostasis is thought to be central to pathologic α-synuclein toxicity; however, the molecular mechanism of this deregulation is poorly understood. Complementary proteomic approaches in cellular and animal models of PD were used to identify and characterize the pathologic α-synuclein interactome. We report that the highest biological processes that interacted with pathologic α-synuclein in mice included RNA processing and translation initiation. Regulation of catabolic processes that include autophagy were also identified. Pathologic α-synuclein was found to bind with the tuberous sclerosis protein 2 (TSC2) and to trigger the activation of the mammalian target of rapamycin (mTOR) complex 1 (mTORC1), which augmented mRNA translation and protein synthesis, leading to neurodegeneration. Genetic and pharmacologic inhibition of mTOR and protein synthesis rescued the dopamine neuron loss, behavioral deficits, and aberrant biochemical signaling in the α-synuclein preformed fibril mouse model and Drosophila transgenic models of pathologic α-synuclein–induced degeneration. Pathologic α-synuclein furthermore led to a destabilization of the TSC1-TSC2 complex, which plays an important role in mTORC1 activity. Constitutive overexpression of TSC2 rescued motor deficits and neuropathology in α-synuclein flies. Biochemical examination of PD postmortem brain tissues also suggested deregulated mTORC1 signaling. These findings establish a connection between mRNA translation deregulation and mTORC1 pathway activation that is induced by pathologic α-synuclein in cellular and animal models of PD.

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Crossref · 10.1126/scitranslmed.add0499

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Authors
Khan, M. R., Yin, X., Kang, S.-U., Mitra, J., Wang, H., Ryu, T., Brahmachari, S., Karuppagounder, S. S., Kimura, Y., Jhaldiyal, A., Kim, H. H., Gu, H., Chen, R., Redding-Ochoa, J., Troncoso, J., Na, C. H., Ha, T., Dawson, V. L., & Dawson, T. M.
Affiliations
  • Johns Hopkins University (US)
  • Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
  • Howard Hughes Medical Institute (US)
Corresponding author
  • Dawson, Valina L.
  • Dawson, Ted M.
Venue
Science Translational Medicine
Published
2023-11-29
Volume
15
Issue
724
Pages
eadd0499-eadd0499
ISSN
  • 1946-6234 (ISSN-L)
  • 1946-6242
OpenAlex
W4389127912
Cited by
64
References
45
Citations by year
2026: 24 · 2025: 31 · 2024: 9
FWCI
9.43
Type
journal article
Language
en
Open access
closed
Locations
  • Science Translational Medicine (publishedVersion)
  • PubMed (publishedVersion)
Topics
  • Health Sciences › Medicine › Neurology › Parkinson's Disease Mechanisms and Treatments
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Nuclear Receptors and Signaling
  • Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
Keywords
Parkinson's disease, mTORC1 signaling, protein synthesis, mRNA translation, TSC2, TSC1/TSC2 complex, proteostasis, autophagy, dopamine neuron loss, Drosophila model, neurodegeneration, motor impairment
MeSH terms
Mechanistic Target of Rapamycin Complex 1, Animals, Disease Models, Animal, Mammals, Parkinson Disease, Tuberous Sclerosis, Proteomics, Mice, alpha-Synuclein, TOR Serine-Threonine Kinases

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