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Direct evidence of Parkinson pathology spread from the gastrointestinal tract to the brain in rats.

Holmqvist, Staffan LU ; Chutna, Oldriska LU ; Bousset, Luc; Aldrin-Kirk, Patrick LU ; Li, Wen LU ; Björklund, Tomas LU ; Wang, Zhan-You; Roybon, Laurent LU ; Melki, Ronald and Li, Jia-Yi LU (2014) In Acta Neuropathologica 128(6). p.805-820
Abstract
The cellular hallmarks of Parkinson's disease (PD) are the loss of nigral dopaminergic neurons and the formation of α-synuclein-enriched Lewy bodies and Lewy neurites in the remaining neurons. Based on the topographic distribution of Lewy bodies established after autopsy of brains from PD patients, Braak and coworkers hypothesized that Lewy pathology primes in the enteric nervous system and spreads to the brain, suggesting an active retrograde transport of α-synuclein (the key protein component in Lewy bodies), via the vagal nerve. This hypothesis, however, has not been tested experimentally thus far. Here, we use a human PD brain lysate containing different forms of α-synuclein (monomeric, oligomeric and fibrillar), and recombinant... (More)
The cellular hallmarks of Parkinson's disease (PD) are the loss of nigral dopaminergic neurons and the formation of α-synuclein-enriched Lewy bodies and Lewy neurites in the remaining neurons. Based on the topographic distribution of Lewy bodies established after autopsy of brains from PD patients, Braak and coworkers hypothesized that Lewy pathology primes in the enteric nervous system and spreads to the brain, suggesting an active retrograde transport of α-synuclein (the key protein component in Lewy bodies), via the vagal nerve. This hypothesis, however, has not been tested experimentally thus far. Here, we use a human PD brain lysate containing different forms of α-synuclein (monomeric, oligomeric and fibrillar), and recombinant α-synuclein in an in vivo animal model to test this hypothesis. We demonstrate that α-synuclein present in the human PD brain lysate and distinct recombinant α-synuclein forms are transported via the vagal nerve and reach the dorsal motor nucleus of the vagus in the brainstem in a time-dependent manner after injection into the intestinal wall. Using live cell imaging in a differentiated neuroblastoma cell line, we determine that both slow and fast components of axonal transport are involved in the transport of aggregated α-synuclein. In conclusion, we here provide the first experimental evidence that different α-synuclein forms can propagate from the gut to the brain, and that microtubule-associated transport is involved in the translocation of aggregated α-synuclein in neurons. (Less)
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author
organization
publishing date
type
Contribution to journal
publication status
published
subject
in
Acta Neuropathologica
volume
128
issue
6
pages
805 - 820
publisher
Springer
external identifiers
  • pmid:25296989
  • wos:000345139100006
  • scopus:84922092995
ISSN
1432-0533
DOI
10.1007/s00401-014-1343-6
language
English
LU publication?
yes
id
1dbd9c9e-58d5-47da-b017-1023588d937a (old id 4737296)
alternative location
http://www.ncbi.nlm.nih.gov/pubmed/25296989?dopt=Abstract
date added to LUP
2014-11-06 19:32:14
date last changed
2017-11-19 03:04:01
@article{1dbd9c9e-58d5-47da-b017-1023588d937a,
  abstract     = {The cellular hallmarks of Parkinson's disease (PD) are the loss of nigral dopaminergic neurons and the formation of α-synuclein-enriched Lewy bodies and Lewy neurites in the remaining neurons. Based on the topographic distribution of Lewy bodies established after autopsy of brains from PD patients, Braak and coworkers hypothesized that Lewy pathology primes in the enteric nervous system and spreads to the brain, suggesting an active retrograde transport of α-synuclein (the key protein component in Lewy bodies), via the vagal nerve. This hypothesis, however, has not been tested experimentally thus far. Here, we use a human PD brain lysate containing different forms of α-synuclein (monomeric, oligomeric and fibrillar), and recombinant α-synuclein in an in vivo animal model to test this hypothesis. We demonstrate that α-synuclein present in the human PD brain lysate and distinct recombinant α-synuclein forms are transported via the vagal nerve and reach the dorsal motor nucleus of the vagus in the brainstem in a time-dependent manner after injection into the intestinal wall. Using live cell imaging in a differentiated neuroblastoma cell line, we determine that both slow and fast components of axonal transport are involved in the transport of aggregated α-synuclein. In conclusion, we here provide the first experimental evidence that different α-synuclein forms can propagate from the gut to the brain, and that microtubule-associated transport is involved in the translocation of aggregated α-synuclein in neurons.},
  author       = {Holmqvist, Staffan and Chutna, Oldriska and Bousset, Luc and Aldrin-Kirk, Patrick and Li, Wen and Björklund, Tomas and Wang, Zhan-You and Roybon, Laurent and Melki, Ronald and Li, Jia-Yi},
  issn         = {1432-0533},
  language     = {eng},
  number       = {6},
  pages        = {805--820},
  publisher    = {Springer},
  series       = {Acta Neuropathologica},
  title        = {Direct evidence of Parkinson pathology spread from the gastrointestinal tract to the brain in rats.},
  url          = {http://dx.doi.org/10.1007/s00401-014-1343-6},
  volume       = {128},
  year         = {2014},
}