1. Trans-synaptic spreading of alpha-synuclein pathology through sensory afferents leads to sensory nerve degeneration and neuropathic pain
- Author
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Ferreira, Nelson, Goncalves, Nadia Pereira, Jan, Asad, Jensen, Nanna Moller, van der Laan, Amelia, Mohseni, Simin, Vaegter, Christian Bjerggaard, Jensen, Poul Henning, Ferreira, Nelson, Goncalves, Nadia Pereira, Jan, Asad, Jensen, Nanna Moller, van der Laan, Amelia, Mohseni, Simin, Vaegter, Christian Bjerggaard, and Jensen, Poul Henning
- Abstract
Pain is a common non-motor symptom of Parkinsons disease (PD), with current limited knowledge of its pathophysiology. Here, we show that peripheral inoculation of mouse alpha-synuclein (alpha-Syn) pre-formed fibrils, in a transgenic mouse model of PD, elicited retrograde trans-synaptic spreading of alpha-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 alpha-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 alpha-Syn pathology with sensory neuron dysfunction and neuropathic impairment, suggesting promising avenues of investigation into the mechanisms underlying pain in PD., Funding Agencies|Independent Research Fund Denmark (IRFD) [8020-00118B]; Lundbeck FoundationLundbeckfonden [R223-2015-4222, R313-2019-606, R248-2016-2518, R171-2014-591]
- Published
- 2021
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