PLK2 disrupts autophagic flux to promote SNCA/α-synuclein pathology DOI Creative Commons
Chuang Zhang, Zhan-Peng Huang, Xinyue Huang

et al.

Autophagy, Journal Year: 2025, Volume and Issue: unknown, P. 1 - 21

Published: Jan. 8, 2025

The aggregation and transmission of SNCA/α-synuclein (synuclein, alpha) is a hallmark pathology Parkinson disease (PD). PLK2 (polo like kinase 2) an evolutionarily conserved serine/threonine that more abundant in the brains all family members, highly expressed PD, linked to SNCA deposition. However, addition its role phosphorylating SNCA, PD mechanisms involved triggering neurodegeneration remain unclear. Here, we found regulated independently S129. Overexpression promoted preformed fibril (PFF)-induced wild-type mutant SNCAS129A. Genetic or pharmacological inhibition attenuated deposition neurotoxicity. Mechanistically, exacerbated propagation by impeding clearance aggregates blocking macroautophagic/autophagic flux. We further showed phosphorylated S1098 DCTN1 (dynactin 1), protein controls movement organelles, leading impaired autophagosome-lysosome fusion. Furthermore, genetic suppression alleviated motor dysfunction vivo. Our findings suggest negatively regulates autophagy, promoting pathology, suggesting for PD.

Language: Английский

Cerium Vanadate Nanozyme with pH-Dependent Dual Enzymatic Activity for Glioblastoma Targeted Therapy and Postradiotherapy Damage Protection DOI Creative Commons
Xiao Han, Boyan Li, Wenhan Wang

et al.

ACS Nano, Journal Year: 2024, Volume and Issue: unknown

Published: July 17, 2024

Nanocatalytic therapy is an emerging technology that uses synthetic nanoscale enzyme mimics for biomedical treatment. However, in the field of neuroscience, achieving neurological protection while simultaneously killing tumor cells a technical challenge. Herein, we synthesized biomimic and translational cerium vanadate (CeVO4) nanozyme glioblastoma (GBM) repair brain damage after GBM ionizing radiation (IR). This system exhibited pH dependence: it showed potent Superoxide dismutase (SOD) activity neutral environment Peroxidase (POD) acidic environment. In cells, this acted lysosomes, causing cellular reactive oxygen species (ROS) accumulation; neuronal could undergo lysosomal escape aggregation with mitochondria, reversing mitochondrial caused by IR restoring expression level antiapoptotic BCL-2 protein. Mechanistically, believe distribution difference related to specific uptake internalization mechanism pathway neurons, ultimately led dual effect nerve vivo model. summary, study provides insight into therapy.

Language: Английский

Citations

5
Autophagy‑regulating miRNAs: Novel therapeutic targets for Parkinson's disease (Review) DOI Creative Commons

Zhenwang Ma,

Hao Liang, Bingcheng Hu

et al.

International Journal of Molecular Medicine, Journal Year: 2023, Volume and Issue: 51(6)

Published: May 2, 2023

Parkinson's disease (PD) is a neurodegenerative disorder that has high incidence during the aging process and characterized by loss of dopaminergic neurons in substantia nigra, leading to motor dysfunctions non‑motor symptoms. Impaired clearance excessive accumulation aberrantly modified proteins or damaged organelles, such as aggregated α‑synuclein dysfunctional mitochondria, are regarded main causes nigrostriatal neurodegeneration. As one major degradation pathways, autophagy can recycle these useless toxic substances maintain cellular homeostasis it plays crucial role PD progression. MicroRNAs (miRNAs) group small non‑coding RNA molecules regulate gene expression silencing targeted mRNAs. Recent studies have illustrated autophagy‑regulating miRNA been implicated pathological processes PD, including accumulation, mitochondrial damage, neuroinflammation neuronal apoptosis, which suggests targeting miRNAs may provide novel therapeutic strategies for this disease. The present review summarizes emphasizes miRNA‑mediated development promising interventions

Language: Английский

Citations

11
Interplay of mitochondria-associated membrane proteins and autophagy: Implications in neurodegeneration DOI
Prakash G. Kulkarni,

Vaibhavi M. Mohire,

Pranjal P. Waghmare

et al.

Mitochondrion, Journal Year: 2024, Volume and Issue: 76, P. 101874 - 101874

Published: March 20, 2024

Language: Английский

Citations

4
Alpha-Synuclein Effects on Mitochondrial Quality Control in Parkinson’s Disease DOI Creative Commons
Liyan Shen, Ulf Dettmer

Biomolecules, Journal Year: 2024, Volume and Issue: 14(12), P. 1649 - 1649

Published: Dec. 22, 2024

The maintenance of healthy mitochondria is essential for neuronal survival and relies upon mitochondrial quality control pathways involved in biogenesis, dynamics, autophagy (mitophagy). Mitochondrial dysfunction critically implicated Parkinson’s disease (PD), a brain disorder characterized by the progressive loss dopaminergic neurons substantia nigra. Consequently, impaired may play key role PD pathology. This affirmed work indicating that genes such as PRKN PINK1, which participate multiple processes, harbor PD-associated mutations. Furthermore, complex-I-inhibiting toxins like MPTP rotenone are known to cause Parkinson-like symptoms. At heart alpha-synuclein (αS), small synaptic protein misfolds aggregates form disease’s hallmark Lewy bodies. specific mechanisms through aggregated αS exerts its neurotoxicity still unknown; however, given vital both PD, an understanding how influences be elucidating pathogenesis discovering future therapeutic targets. Here, current knowledge relationship between reviewed, highlighting recent findings regarding effects on autophagy.

Language: Английский

Citations

4
PLK2 disrupts autophagic flux to promote SNCA/α-synuclein pathology DOI Creative Commons
Chuang Zhang, Zhan-Peng Huang, Xinyue Huang

et al.

Autophagy, Journal Year: 2025, Volume and Issue: unknown, P. 1 - 21

Published: Jan. 8, 2025

The aggregation and transmission of SNCA/α-synuclein (synuclein, alpha) is a hallmark pathology Parkinson disease (PD). PLK2 (polo like kinase 2) an evolutionarily conserved serine/threonine that more abundant in the brains all family members, highly expressed PD, linked to SNCA deposition. However, addition its role phosphorylating SNCA, PD mechanisms involved triggering neurodegeneration remain unclear. Here, we found regulated independently S129. Overexpression promoted preformed fibril (PFF)-induced wild-type mutant SNCAS129A. Genetic or pharmacological inhibition attenuated deposition neurotoxicity. Mechanistically, exacerbated propagation by impeding clearance aggregates blocking macroautophagic/autophagic flux. We further showed phosphorylated S1098 DCTN1 (dynactin 1), protein controls movement organelles, leading impaired autophagosome-lysosome fusion. Furthermore, genetic suppression alleviated motor dysfunction vivo. Our findings suggest negatively regulates autophagy, promoting pathology, suggesting for PD.

Language: Английский

Citations

0