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Szegö EM, Van den Haute C, Höfs L, et al. Rab7 reduces α-synuclein toxicity in rats and primary neurons. Exp Neurol. 2021;347:113900doi: 10.1016/j.expneurol.2021.113900.
Szegö, E. M., Van den Haute, C., Höfs, L., Baekelandt, V., Van der Perren, A., & Falkenburger, B. H. (2022). Rab7 reduces α-synuclein toxicity in rats and primary neurons. Experimental neurology, 347113900. https://doi.org/10.1016/j.expneurol.2021.113900
Szegö, Eva M, et al. "Rab7 reduces α-synuclein toxicity in rats and primary neurons." Experimental neurology vol. 347 (2022): 113900. doi: https://doi.org/10.1016/j.expneurol.2021.113900
Szegö EM, Van den Haute C, Höfs L, Baekelandt V, Van der Perren A, Falkenburger BH. Rab7 reduces α-synuclein toxicity in rats and primary neurons. Exp Neurol. 2022 Jan;347:113900. doi: 10.1016/j.expneurol.2021.113900. Epub 2021 Oct 22. PMID: 34695425.
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Exp Neurol. 2022 Jan;347:113900. doi: 10.1016/j.expneurol.2021.113900. Epub 2021 Oct 22.

Rab7 reduces α-synuclein toxicity in rats and primary neurons.

Experimental neurology

Eva M Szegö, Chris Van den Haute, Lennart Höfs, Veerle Baekelandt, Anke Van der Perren, Björn H Falkenburger

Affiliations

  1. Department of Neurology, TU Dresden, Dresden, Germany. Electronic address: [email protected].
  2. Laboratory for Neurobiology and Gene Therapy, Department of Neurosciences, Leuven Brain Institute, KU Leuven, Leuven, Belgium; Leuven Viral Vector Core, KU Leuven, Leuven, Belgium. Electronic address: [email protected].
  3. Department of Neurology, TU Dresden, Dresden, Germany. Electronic address: [email protected].
  4. Laboratory for Neurobiology and Gene Therapy, Department of Neurosciences, Leuven Brain Institute, KU Leuven, Leuven, Belgium; Leuven Viral Vector Core, KU Leuven, Leuven, Belgium. Electronic address: [email protected].
  5. Laboratory for Neurobiology and Gene Therapy, Department of Neurosciences, Leuven Brain Institute, KU Leuven, Leuven, Belgium. Electronic address: [email protected].
  6. Department of Neurology, TU Dresden, Dresden, Germany; Deutsches Zentrum für Neurodegenerative Erkrankungen, Dresden, Germany; Department of Neurology, RWTH Aachen University, Aachen, Germany; JARA-BRAIN Institute Molecular Neuroscience and Neuroimaging, Forschungszentrum Jülich GmbH and RWTH Aachen University, Aachen, Germany. Electronic address: [email protected].

PMID: 34695425 DOI: 10.1016/j.expneurol.2021.113900

Abstract

During the pathogenesis of Parkinson's disease (PD), aggregation of alpha-synuclein (αSyn) induces a vicious cycle of cellular impairments that lead to neurodegeneration. Consequently, removing toxic αSyn aggregates constitutes a plausible strategy against PD. In this work, we tested whether stimulating the autolysosomal degradation of αSyn aggregates through the Ras-related in brain 7 (Rab7) pathway can reverse αSyn-induced cellular impairment and prevent neurodegeneration in vivo. The disease-related A53T mutant of αSyn was expressed in primary neurons and in dopaminergic neurons of the rat brain simultaneously with wild type (WT) Rab7 or the T22N mutant as negative control. The cellular integrity was quantified by morphological and biochemical analyses. In primary neurons, WT Rab7 rescued the αSyn-induced loss of neurons and neurites. Furthermore, Rab7 decreased the amount of reactive oxygen species and the amount of Triton X-100 insoluble αSyn. In rat brain, WT Rab7 reduced αSyn-induced loss of dopaminergic axon terminals in the striatum and the loss of dopaminergic dendrites in the substantia nigra pars reticulata. Further, WT Rab7 lowered αSyn pathology as quantified by phosphorylated αSyn staining. Finally, WT Rab7 attenuated αSyn-induced DNA damage in primary neurons and rat brain. In brief, Rab7 reduced αSyn-induced pathology, ameliorated αSyn-induced neuronal degeneration, oxidative stress and DNA damage. These findings indicate that Rab7 is able to disrupt the vicious cycle of cellular impairment, αSyn pathology and neurodegeneration present in PD. Stimulation of Rab7 and the autolysosomal degradation pathway could therefore constitute a beneficial strategy for PD.

Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.

Keywords: Autophagy; DNA damage; Neuroprotection; Oxidative stress; Parkinson's disease; Protein aggregation; Rab7; alpha-Synuclein

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