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  3. Trans-synaptic spreading of alpha-synuclein pathology through sensory afferents leads to sensory nerve degeneration and neuropathic pain

Trans-synaptic spreading of alpha-synuclein pathology through sensory afferents leads to sensory nerve degeneration and neuropathic pain

  • Acta Neuropathol Commun. 2021 Feb 25;9(1):31. doi: 10.1186/s40478-021-01131-8.
Nelson Ferreira  # 1,  Nádia Pereira Gonçalves  # 2 3,  Asad Jan 4,  Nanna Møller Jensen 4,  Amelia van der Laan 4,  Simin Mohseni 5,  Christian Bjerggaard Vægter 4 6,  Poul Henning Jensen 7
Affiliations

Affiliations

  • 1 Danish Research Institute of Translational Neuroscience (DANDRITE), Nordic EMBL Partnership for Molecular Medicine, Department of Biomedicine, Aarhus University, 8000, Aarhus C, Denmark. nelson@biomed.au.dk.
  • 2 Danish Research Institute of Translational Neuroscience (DANDRITE), Nordic EMBL Partnership for Molecular Medicine, Department of Biomedicine, Aarhus University, 8000, Aarhus C, Denmark. npg@dandrite.au.dk.
  • 3 International Diabetic Neuropathy Consortium (IDNC), Aarhus University Hospital, Aarhus N, Denmark. npg@dandrite.au.dk.
  • 4 Danish Research Institute of Translational Neuroscience (DANDRITE), Nordic EMBL Partnership for Molecular Medicine, Department of Biomedicine, Aarhus University, 8000, Aarhus C, Denmark.
  • 5 Department of Biomedical and Clinical Sciences, Linköping University, Linköping, Sweden.
  • 6 International Diabetic Neuropathy Consortium (IDNC), Aarhus University Hospital, Aarhus N, Denmark.
  • 7 Danish Research Institute of Translational Neuroscience (DANDRITE), Nordic EMBL Partnership for Molecular Medicine, Department of Biomedicine, Aarhus University, 8000, Aarhus C, Denmark. phj@biomed.au.dk.
  • # Contributed equally.
PMID: 33632316 DOI: 10.1186/s40478-021-01131-8
Abstract

Pain is a common non-motor symptom of Parkinson's disease (PD), with current limited knowledge of its pathophysiology. Here, we show that peripheral inoculation of mouse alpha-synuclein (α-Syn) pre-formed fibrils, in a transgenic mouse model of PD, elicited retrograde trans-synaptic spreading of α-Syn pathology (pSer129) across sensory neurons and dorsal nerve roots, reaching central pain processing regions, including the spinal dorsal horn and the projections of the anterolateral system in the central nervous system (CNS). Pathological peripheral to CNS propagation of α-Syn aggregates along interconnected neuronal populations within sensory afferents, was concomitant with impaired nociceptive response, reflected by mechanical allodynia, reduced nerve conduction velocities (sensory and motor) and degeneration of small- and medium-sized myelinated fibers. Our findings show a link between the transneuronal propagation of α-Syn pathology with sensory neuron dysfunction and neuropathic impairment, suggesting promising avenues of investigation into the mechanisms underlying pain in PD.

Keywords

Alpha-synuclein; Neuropathic pain; Nociception; Parkinson’s disease; Protein aggregation.

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