2. Academic Validation
  3. PLK2 disrupts autophagic flux to promote SNCA/α-synuclein pathology

PLK2 disrupts autophagic flux to promote SNCA/α-synuclein pathology

  • Autophagy. 2025 Jan 14:1-21. doi: 10.1080/15548627.2024.2448914.
Chuang Zhang 1,  Zhanpeng Huang 1,  Xinyue Huang 1,  Yanni Ma 1,  Yifan Cao 1,  Zhixiong Zhang 1,  Rui Wang 1,  Haigang Ren 1 2 3 4,  Longtai Zheng 1,  Chun-Feng Liu 5,  Guanghui Wang 1 3 6
Affiliations

Affiliations

  • 1 Laboratory of Molecular Neuropathology, Department of Pharmacology, Jiangsu Key Laboratory of Neuropsychiatric Diseases and College of Pharmaceutical Sciences, Soochow University, Suzhou, Jiangsu, China.
  • 2 Department of Pharmacy, The Affiliated Zhangjiagang Hospital of Soochow University, Suzhou, Jiangsu, China.
  • 3 MOE Key Laboratory of Geriatric Diseases and Immunology, Soochow University, Suzhou, Jiangsu, China.
  • 4 Jiangsu Provincial Medical Innovation Center of Trauma Medicine, Institute of Trauma Medicine, Suzhou, Jiangsu, China.
  • 5 Department of Neurology and Clinical Research Center of Neurological Disease, the Second Affiliated Hospital of Soochow University, Suzhou, Jiangsu, China.
  • 6 Suzhou Key Laboratory of Geriatric Neurological Disorders, Center of Translational Medicine, the First People's Hospital of Taicang, Taicang Affiliated Hospital of Soochow University, Suzhou, Jiangsu, China.
PMID: 39773002 DOI: 10.1080/15548627.2024.2448914
Abstract

The aggregation and transmission of SNCA/α-synuclein (synuclein, alpha) is a hallmark pathology of Parkinson disease (PD). PLK2 (polo like kinase 2) is an evolutionarily conserved serine/threonine kinase that is more abundant in the brains of all family members, is highly expressed in PD, and is linked to SNCA deposition. However, in addition to its role in phosphorylating SNCA, the role of PLK2 in PD and the mechanisms involved in triggering neurodegeneration remain unclear. Here, we found that PLK2 regulated SNCA pathology independently of S129. Overexpression of PLK2 promoted SNCA preformed fibril (PFF)-induced aggregation of wild-type SNCA and mutant SNCAS129A. Genetic or pharmacological inhibition of PLK2 attenuated SNCA deposition and neurotoxicity. Mechanistically, PLK2 exacerbated the propagation of SNCA pathology by impeding the clearance of SNCA aggregates by blocking macroautophagic/autophagic flux. We further showed that PLK2 phosphorylated S1098 of DCTN1 (dynactin 1), a protein that controls the movement of organelles, leading to impaired autophagosome-lysosome fusion. Furthermore, genetic suppression of PLK2 alleviated SNCA aggregation and motor dysfunction in vivo. Our findings suggest that PLK2 negatively regulates Autophagy, promoting SNCA pathology, suggesting a role for PLK2 in PD.Abbreviation: AD: Alzheimer disease; AMPK: AMP-activated protein kinase; CASP3: Caspase 3; DCTN1: dynactin 1; LBs: lewy bodies; LDH: lactate dehydrogenase; LAMP1: lysosomal associated membrane protein 1; MAP1LC3/LC3: microtubule associated protein 1 light chain 3; MAP2: microtubule associated protein 2; MTOR: mechanistic target of rapamycin kinase; NH4Cl: ammonium chloride; p-SNCA: phosphorylation of SNCA at S129; PD: Parkinson disease; PFF: preformed fibril; PI: propidium iodide; PLK2: polo like kinase 2; PRKAA/AMPK: protein kinase AMP-activated catalytic subunit alpha; shRNA: short hairpin RNA; SNCA: synuclein, alpha; SQSTM1/p62: sequestosome 1; TH: tyrosine hydroxylase; TX: Triton X-100; ULK1: unc-51 like Autophagy activating kinase 1.

Keywords

Autophagic flux; DCTN1; PLK2; Parkinson disease; autophagosome-lysosome fusion.

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