Original Paper

Acta Neuropathologica

, Volume 128, Issue 6, pp 805-820

First online:

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

  • Staffan HolmqvistAffiliated withNeural Plasticity and Repair Unit, Department of Experimental Medical Science, Wallenberg Neuroscience Center, Lund UniversityCell Stem Cell Laboratory for CNS Disease Modeling, Department of Experimental Medical Science, MultiPark Strategic Research Area and Lund Stem Cell Center, Lund University
  • , Oldriska ChutnaAffiliated withNeural Plasticity and Repair Unit, Department of Experimental Medical Science, Wallenberg Neuroscience Center, Lund University
  • , Luc BoussetAffiliated withLaboratoire d’Enzymologie et de Biochimie Structurale, CNRS
  • , Patrick Aldrin-KirkAffiliated withMolecular Neuromodulation Unit, Department of Experimental Medical Science, MultiPark Strategic Research Area, Wallenberg Neuroscience Center, Lund University
  • , Wen LiAffiliated withNeural Plasticity and Repair Unit, Department of Experimental Medical Science, Wallenberg Neuroscience Center, Lund University
  • , Tomas BjörklundAffiliated withMolecular Neuromodulation Unit, Department of Experimental Medical Science, MultiPark Strategic Research Area, Wallenberg Neuroscience Center, Lund University
  • , Zhan-You WangAffiliated withCollege of Life and Health Sciences, Institute of Neuroscience, Northeastern University
  • , Laurent RoybonAffiliated withCell Stem Cell Laboratory for CNS Disease Modeling, Department of Experimental Medical Science, MultiPark Strategic Research Area and Lund Stem Cell Center, Lund University
  • , Ronald MelkiAffiliated withLaboratoire d’Enzymologie et de Biochimie Structurale, CNRS
    • , Jia-Yi LiAffiliated withNeural Plasticity and Repair Unit, Department of Experimental Medical Science, Wallenberg Neuroscience Center, Lund UniversityCollege of Life and Health Sciences, Institute of Neuroscience, Northeastern University Email author 

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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.

Keywords

Parkinson’s disease Alpha-synuclein Lewy body Protein aggregation Protein propagation