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  Impact of alpha-synuclein spreading on the nigrostriatal dopaminergic pathway depends on the onset of the pathology

Sun, F., Salinas, A. G., Filser, S., Blumenstock, S., Medina-Luque, J., Herms, J., et al. (2022). Impact of alpha-synuclein spreading on the nigrostriatal dopaminergic pathway depends on the onset of the pathology. Brain Pathology, 32(2): e13036. doi:10.1111/bpa.13036.

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 Creators:
Sun, Fanfan, Author
Salinas, Armando G., Author
Filser, Severin, Author
Blumenstock, Sonja1, Author           
Medina-Luque, Jose, Author
Herms, Jochen, Author
Sgobio, Carmelo, Author
Affiliations:
1Research Group: Molecular Neurodegeneration / Dudanova, MPI of Neurobiology, Max Planck Society, ou_3060199              

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Free keywords: PARKINSONS-DISEASE; SUBSTANTIA-NIGRA; HIGH-AFFINITY; DYSFUNCTION; TRANSMISSION; DEMENTIA; OLIGOMERIZATION; FIBRILLIZATION; INCLUSIONS; EXPRESSIONNeurosciences & Neurology; Pathology; dopamine; neurotransmission; nigrostriatal pathway; PFFs; spreading; alpha-synuclein;
 Abstract: Misfolded alpha-synuclein spreads along anatomically connected areas through the brain, prompting progressive neurodegeneration of the nigrostriatal pathway in Parkinson's disease. To investigate the impact of early stage seeding and spreading of misfolded alpha-synuclein along with the nigrostriatal pathway, we studied the pathophysiologic effect induced by a single acute alpha-synuclein preformed fibrils (PFFs) inoculation into the midbrain. Further, to model the progressive vulnerability that characterizes the dopamine (DA) neuron life span, we used two cohorts of mice with different ages: 2-month-old (young) and 5-month-old (adult) mice. Two months after a-synuclein PFFs injection, we found that striatal DA release decreased exclusively in adult mice. Adult DA neurons showed an increased level of pathology spreading along with the nigrostriatal pathway accompanied with a lower volume of alpha-synuclein deposition in the midbrain, impaired neurotransmission, rigid DA terminal composition, and less microglial reactivity compared with young neurons. Notably, preserved DA release and increased microglial coverage in the PFFs-seeded hemisphere coexist with decreased large-sized terminal density in young DA neurons. This suggests the presence of a targeted pruning mechanism that limits the detrimental effect of alpha-synuclein early spreading. This study suggests that the impact of the pathophysiology caused by misfolded alpha-synuclein spreading along the nigrostriatal pathway depends on the age of the DA network, reducing striatal DA release specifically in adult mice.

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Language(s): eng - English
 Dates: 2022-03-01
 Publication Status: Published in print
 Pages: 18
 Publishing info: -
 Table of Contents: -
 Rev. Type: -
 Identifiers: ISI: 000720783200001
DOI: 10.1111/bpa.13036
 Degree: -

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Title: Brain Pathology
  Other : Brain Pathol.
Source Genre: Journal
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Publ. Info: Zürich, Switzerland : International Society of Neuropathology
Pages: - Volume / Issue: 32 (2) Sequence Number: e13036 Start / End Page: - Identifier: ISSN: 1015-6305
CoNE: https://pure.mpg.de/cone/journals/resource/954925585260