Dataset Information

Synphilin-1 upregulates RBL2 expression and causes a G0/G1 phase cell cycle arrest in the neurons

ABSTRACT: Synphilin-1, a major component of Lewy bodies in the brain of Parkinsons disease (PD) patients, is a cytoplasmic protein that interacts with alpha-synuclein and is suggested to have cytoprotective effects in the neuronal cells. alpha-Synuclein overexpression induced re-entry of the neuronal cells into the cell cycle, which is associated with neuronal death. However, the role of synphilin-1 in cell cycle progression remains unelucidated. Here, we aimed at investigating the role of synphilin-1 in cell cycle progression using human embryonic kidney (HEK) 293 cells, human neuroblastoma SH-SY5Y cells, and post-mortem brains of PD patients.

INSTRUMENT(S): Orbitrap Fusion Lumos

ORGANISM(S): Mus <mouse, Genus> (ncbitaxon:10088)

SUBMITTER: Gwang Lee

PROVIDER: MSV000089926 | MassIVE | Wed Jul 20 03:05:00 BST 2022

REPOSITORIES: MassIVE

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Publications

Synphilin-1 regulates mechanotransduction in rigidity sensing through interaction with zyxin.

Kim Seok Gi SG Li Jinyan J Hwang Ji Su JS Hassan Muhammad Anwar Ul MAU Sim Ye Eun YE Lee Ju Yeon JY Mo Jung-Soon JS Kim Myeong Ok MO Lee Gwang G Park Sungsu S

Journal of nanobiotechnology 20250514 1

<h4>Background</h4>Synphilin-1 has been studied extensively in the context of Parkinson's disease pathology. However, the biophysical functions of synphilin-1 remain unexplored. To investigate its novel functionalities herein, cellular traction force and rigidity sensing ability are analyzed based on synphilin-1 overexpression using elastomeric pillar arrays and substrates of varying stiffness. Molecular changes are analyzed using RNA sequencing-based transcriptomic and liquid chromatography-tan ...[more]

PMID: 40369541

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Project description:Abnormal accumulation of aggregated proteins and sustained microglial activation are important contributors of neurodegenerative process in neurological diseases. Recent studies have shown that aggregation-prone proteins, such as a-synuclein, the protein implicated in Parkinson’s disease (PD), are released from neuronal cells and thus present in the extracellular fluid, pointing to the possible paracrine effects of these proteins on microglial immune responses. However, the mechanism underlying the disease-associated microglial activation and the role of neuronal proteins in this process remain unknown. Here, we show that extracellular a-synuclein released from neuronal cells is an endogenous ligand of toll-like receptor 2 (TLR2) and activates microglia, which in turn induces neurodegeneration. Interaction between neuron-released a-synuclein and TLR2 and subsequent activation of the TLR2 signaling were demonstrated comprehensively by using computational modeling of signaling network and by the experimental validation in TLR2-deficient microglia both in vitro and in vivo. In contrast to the neuron-released a-synuclein, recombinant a-synuclein proteins, including monomer, oligomer, fibril, or nitrated forms, were not able to interact or activate TLR2, suggesting that neuronal cells have a mechanism of enriching specific forms of a-synuclein capable of activating TLR2 during the process of releasing this protein. Taken together, the results suggest that both neuron-released extracellular a-synuclein and TLR2 might be novel therapeutic targets for modifying neuroinflammation in PD and related neurodegenerative diseases. We collected culture media from differentiated SH-SY5Y cells overexpressing either human a-synuclein (alpha-SCM) or beta-galactosidase (LZCM) and treat these media to primary rat microglia at the concentration of a-synuclein of 1.1M. Transcriptome analyses with microglial cells treated with either aSCM or LZCM at two different time points, 6 h and 24 h.