title: Transfer of host-derived α 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 α 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 α synuclein (AAV2/6-α synuclein) or green fluorescent protein (AAV2/6-GFP) into the striatum rostral to the grafts. Care was taken to make sure that 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 α synuclein but none of the grafted cells expressed host-derived GFP. The α 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 α 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.
authors: Department of Neurological Sciences, Rush University Medical Center, Chicago, Illinois 60612, USA. jkordowe@rush.edu
authors: Jeffrey H
authors: JH
authors: Kordower
authors: Hemraj B
authors: HB
authors: Dodiya
authors: Adam M
authors: AM
authors: Kordower
authors: Brian
authors: B
authors: Terpstra
authors: Katrina
authors: K
authors: Paumier
authors: Lalitha
authors: L
authors: Madhavan
authors: Caryl
authors: C
authors: Sortwell
authors: Kathy
authors: K
authors: Steece-Collier
authors: Timothy J
authors: TJ
authors: Collier
references: Proc Natl Acad Sci U S A. 2009 Aug 4;106(31):13010-5
references: 19651612
references: Mov Disord. 2008 Dec 15;23(16):2303-6
references: 19006193
references: Neurobiol Dis. 2009 Sep;35(3):385-98
references: 19505575
references: Mov Disord. 2010 Jun 15;25(8):1091-6
references: 20198645
references: Nat Rev Neurosci. 2008 Oct;9(10):741-5
references: 18769444
references: J Comp Neurol. 1994 Nov 1;349(1):20-35
references: 7852624
references: Nat Med. 2008 May;14(5):501-3
references: 18391963
references: J Neurosci. 2005 Jun 22;25(25):6016-24
references: 15976091
references: J Clin Invest. 2011 Feb;121(2):715-25
references: 21245577
references: Nat Med. 2008 May;14(5):504-6
references: 18391962
references: Neurobiol Dis. 2007 Jan;25(1):134-49
references: 17055279
references: J Comp Neurol. 2009 Jul 1;515(1):15-30
references: 19399877
references: Ann Neurol. 2002 Aug;52(2):205-10
references: 12210791
references: Lancet Neurol. 2010 Nov;9(11):1128-38
references: 20846907
references: Neurobiol Aging. 1993 Jul-Aug;14(4):275-85
references: 8367009
references: Neurosci Lett. 2006 Mar 20;396(1):67-72
references: 16330147
references: Neurosci Lett. 1999 Jul 2;269(1):13-6
references: 10821633
references: Nat Rev Mol Cell Biol. 2010 Apr;11(4):301-7
references: 20308987
references: J Microsc. 1987 Sep;147(Pt 3):229-63
references: 3430576
references: Ann N Y Acad Sci. 2010 Jan;1184:55-67
references: 20146690