α‐Synuclein: The Long Distance Runner

Abstract

Parkinson's disease is characterized by α-synuclein pathology in the form of Lewy bodies and Lewy neurites. Braak et al described the spatial and temporal spread of α-synuclein pathology in Parkinson's disease. Recent experimental studies have demonstrated that α-synuclein can transfer from cell to cell. In this review, we highlight the involvement of α-synuclein in Parkinson's disease and in Braak's staging of Parkinson's disease pathology. We discuss whether a prion-like mechanism of α-synuclein spread might contribute to Parkinson's disease pathology. We describe recent studies investigating cell-to-cell transfer of α-synuclein and focus our review on the long-distance axonal transport of α-synuclein along neurons.

Potential Pathways of Abnormal Tau and α-Synuclein Dissemination in Sporadic Alzheimer's and Parkinson's Diseases

“…From there, the hypothesis was that Lewy pathology might reach the dmX in the lower brainstem via the myenteric plexus and retrograde axonal transport through unmyelinated axons of the peripheral vagus nerve (Braak et al 2003b;Hawkes et al 2007;Braak and Del Tredici 2009; see also George et al 2013;Olanow and Brundin 2013;Holmqvist et al 2014;Ulusoy et al 2014).…”

“…In in vitro (Volpicelli-Daley et al 2011;Freundt et al 2012) and animal models (Recasens et al 2014), misfolded a-synuclein is capable of both retrograde and anterograde axonal transport (see also George et al 2013). Thus, despite the lack of verifiable evidence in human autopsy cases to date and although neither the olfactory mucosa, olfactory fila, nor olfactory glomerula have been reported to develop a-synuclein aggregates (Duda et al 1999), both of the following additional routes of a-synuclein propagation during stages 1 and 2 are conceivable from an anatomical standpoint: (1) a-Synuclein could disseminate to the locus coeruleus in stage 2 by retrograde transport and transsynaptic transmission from the OB and anterior olfactory nucleus (stage 1) (Shipley et al 1985;Marien et al 2004;Doty 2008).…”

“…The pathology could consist of misfolded a-synuclein molecules, minimally aggregated inclusions, or fragments of both, and be capable of inducing conformational changes in normal a-synuclein within previously uninvolved recipient neurons. As in tau models of AD, there is also some experimental evidence that a-synuclein can be taken up into neurons by endocytosis (Desplats et al 2009;Luk et al 2009;Nonaka et al 2010;Hansen et al 2011;Volpicelli-Daley et al 2011;George et al 2013). Most of the misfolded a-synuclein molecules ( presumably originating in synaptic terminals) would be transported via the axon in a retrograde direction to the soma to undergo proteosomal or other forms of degradation.…”

“…Notably, all brain regions and all types of nerve cells consecutively involved in AD or PD are anatomically interconnected over considerable distances, thereby indicating that physical contact among such interconnected nerve cells plays a key role in the pathogenesis of both illnesses (Pearson et al 1985;Saper et al 1987;Pearson and Powell 1989;Pearson 1996;Duyckaerts et al 1997;Braak and Del Tredici 2011b). Ab is deposited extracellularly and thus is not known to transfer from one nerve cell to the next in the neuronal chain (Fiala 2007;Kaufman and Diamond 2013).Here, we focus on potential pathways and mechanisms related to the postulated transmission and transneuronal dissemination of tau and a-synuclein between involved neurons and as yet uninvolved neurons in anatomically connected regions (Brundin et al 2008Clavaguera et al 2009Clavaguera et al , 2013aDesplats et al 2009;Luk et al 2009;Angot et al 2010 Angot et al , 2012Frost and Diamond 2010;Goedert et al 2010;Lee et al 2010;Nonaka et al 2010;Dunning et al 2011; Lee 2011, 2014;Hansen et al 2011;Jucker and Walker 2011;Kordower et al 2011;Lee et al 2011;Volpicelli-Daley et al 2011;Hansen and Li 2012;Holmes and Diamond 2012;Liu et al 2012; Luk et al 2012a,b;Mougenot et al 2012;Polymenidou and Cleveland 2012;Walker et al 2012;Duyckaerts 2013;George et al 2013;Iba et al 2013;…”

“…Here, we focus on potential pathways and mechanisms related to the postulated transmission and transneuronal dissemination of tau and a-synuclein between involved neurons and as yet uninvolved neurons in anatomically connected regions (Brundin et al 2008Clavaguera et al 2009Clavaguera et al , 2013aDesplats et al 2009;Luk et al 2009;Angot et al 2010Angot et al , 2012Frost and Diamond 2010;Goedert et al 2010; Lee et al 2010;Nonaka et al 2010;Dunning et al 2011;Lee 2011, 2014;Hansen et al 2011;Jucker and Walker 2011;Kordower et al 2011;Lee et al 2011;Volpicelli-Daley et al 2011;Hansen and Li 2012;Holmes and Diamond 2012;Liu et al 2012;Luk et al 2012a,b;Mougenot et al 2012;Polymenidou and Cleveland 2012;Walker et al 2012;Duyckaerts 2013;George et al 2013;Iba et al 2013;Masuda-Suzukake et al 2013;Olanow and Brundin 2013;Rey et al 2013;Van Ba et al 2013;Wu et al 2013;Ahmed et al 2014;Dujardin et al 2014;Holmqvist et al 2014;Recasens et al 2014;Calafate et al 2015).…”