Journal Article

DZNE-2021-01329

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png Rab7 reduces α-synuclein toxicity in rats and primary neurons.

Szegö, E. M. ; Van den Haute, C. ; Höfs, L. ; Baekelandt, V. ; Van der Perren, A. ; Falkenburger, B. (Last author)DZNE*

2022
Academic Press Orlando, Fla.

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Please use a persistent id in citations: 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.

Keyword(s): Animals (MeSH) ; Cells, Cultured (MeSH) ; DNA Damage: drug effects (MeSH) ; DNA Damage: physiology (MeSH) ; Dopaminergic Neurons: drug effects (MeSH) ; Dopaminergic Neurons: metabolism (MeSH) ; Dopaminergic Neurons: pathology (MeSH) ; Female (MeSH) ; Humans (MeSH) ; Male (MeSH) ; Mice (MeSH) ; Mice, Inbred C57BL (MeSH) ; Oxidative Stress: drug effects (MeSH) ; Oxidative Stress: physiology (MeSH) ; Rats (MeSH) ; Rats, Wistar (MeSH) ; Reactive Oxygen Species: metabolism (MeSH) ; alpha-Synuclein: biosynthesis (MeSH) ; alpha-Synuclein: toxicity (MeSH) ; rab7 GTP-Binding Proteins: biosynthesis (MeSH) ; rab7 GTP-Binding Proteins: pharmacology (MeSH) ; Autophagy ; DNA damage ; Neuroprotection ; Oxidative stress ; Parkinson's disease ; Protein aggregation ; Rab7 ; alpha-Synuclein

Note: (CC BY-NC-ND)

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Contributing Institute(s):

1. Clinical Study Team Dresden (Clinical Study Team Dresden ; AG Falkenburger)

Research Program(s):

1. 353 - Clinical and Health Care Research (POF4-353) (POF4-353)

Appears in the scientific report 2022

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Database coverage:
; ; ; BIOSIS Previews ; Biological Abstracts ; Clarivate Analytics Master Journal List ; Current Contents - Life Sciences ; Ebsco Academic Search ; Essential Science Indicators ; IF >= 5 ; JCR ; Nationallizenz ; SCOPUS ; Science Citation Index Expanded ; Web of Science Core Collection

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