Transfer of host-derived alpha synuclein to grafted dopaminergic neurons in rat

Abstract

Multiple laboratories have recently demonstrated that long-term dopaminergic transplants form Lewy bodies in patients with Parkinson’s disease. Debate has arisen as to whether these Lewy bodies form from the transfer of alpha synuclein from the host to the graft or whether they form from intrinsic responses of the graft from being placed into what was, or became, an inflammatory focus. To test whether the former hypothesis was possible, we grafted fetal rat ventral mesencephalon into the dopamine depleted striatum of rats that had previously received 6-hydroxydopamine lesions. One month after the transplant, rats received viral over expression of human alpha synuclein (AAV2/6 - alpha synuclein) or green fluorescent protein (AAV2/6-GFP) into the striatum rostral to the grafts. Care was taken to make sure the AAV injections were sufficiently distal to the graft so no cells would be directly transfected. All rats were sacrificed five weeks after the virus injections. Double label immunohistochemistry combined with confocal microscopy revealed that a small number of grafted tyrosine hydroxylase (TH) neurons (5.7%+ 1.5% (mean + SEM) of grafted dopamine cells) expressed host derived alpha synuclein but none of the grafted cells expressed host-derived GFP. The alpha synuclein in a few of these cells was misfolded and failed to be digested with proteinase K. These data indicate that it is possible for host derived alpha synuclein to transfer to grafted neurons supporting the concept that this is one possible mechanism by which grafted dopamine neurons form Lewy bodies in Parkinson’s disease patients.

Parkinson's Disease and Parkinsonism: Neuropathology

“…Subsequent iterations of the Braak scheme proposed that autonomic neurons in peripheral nervous system may be affected before involvement of the central nervous system ) and this has prompted recognition that PD is a multiorgan disease process, not merely a disorder of central nervous system (Beach et al 2010). Moreover, it has fed the debate on cell-to-cell transmission of unknown putative disease factors ( prion-like) (Hawkes et al 2009), especially given the fact that fetal mesencephalic intrastriatal transplants to treat PD have been shown to develop Lewy body pathology (Kordower et al 2008), possibly by cellto-cell transmission (Kordower et al 2011). …”

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

“…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;…”

Corruption and Spread of Pathogenic Proteins in Neurodegenerative Diseases

“…When fetal dopaminergic neurons were transplanted into the striatum of Parkinsonian patients, some of the cells eventually manifested ␣-synuclein-positive Lewy bodies, indicative of the seeded induction of synucleinopathy in the transplanted tissue by proteopathic ␣-synuclein seeds stemming from the host (77,78). Confirmatory findings for the seeding and dispersion of synucleinopathy have been reported in vitro (79 -81) and in experimental animals (79,80,(82)(83)(84).…”