English
 
Help Privacy Policy Disclaimer
  Advanced SearchBrowse

Item

ITEM ACTIONSEXPORT

Released

Journal Article

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

MPS-Authors
/persons/resource/persons243380

Blumenstock,  Sonja
Research Group: Molecular Neurodegeneration / Dudanova, MPI of Neurobiology, Max Planck Society;

External Resource
No external resources are shared
Fulltext (restricted access)
There are currently no full texts shared for your IP range.
Fulltext (public)

bpa.13036.pdf
(Publisher version), 3MB

Supplementary Material (public)
There is no public supplementary material available
Citation

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.


Cite as: http://hdl.handle.net/21.11116/0000-0009-988D-D
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.