Transneuronal Propagation of Pathologic ?-Synuclein from the Gut to the Brain Models Parkinson?s disease. Sangjune Kim1,2, Seung-Hwan Kwon1,2, Seung Pil Yun1,2, Tae-In Kam1,2, Nikhil Panicker1,2, Senthilkumar S. Karuppagounder1,2, Saebom Lee1,2, Jun Hee Lee1,2,10, Wonjoong Richard Kim1,2, Minjee Kook1,2, Catherine A. Foss3, Chentian Shen3,11, Subhash Kulkarni4, Pankaj J. Pasricha4, Gabsang Lee1,2,5, Martin G. Pomper3, Valina L. Dawson1,2,5,6,8, Ted M. Dawson1,2,5,7,8,9,#, and Han Seok Ko1,2,8,9,# 1Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering, 2Department of Neurology, 3The Russell H. Morgan Department of Radiology and Radiological Science, 4Center for Neurogastroenterology, Department of Medicine, 5Solomon H. Snyder Department of Neuroscience, 6Department of Physiology, 7Department of Pharmacology and Molecular Sciences, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA 8Adrienne Helis Malvin Medical Research Foundation, 9Diana Helis Henry Medical Research Foundation, New Orleans, LA 70130, USA Present Address: 10Department of Pharmacology and Toxicology, University of Alabama at Birmingham School of Medicine, Birmingham, AL 35294, USA 11Department of Nuclear Medicine, Shanghai Jiao Tong University Affiliated Sixth People?s Hospital, Shanghai 200233, China #Correspondence: (T.M.D.), (H.S.K.) Analysis of human pathology led to the Braak hypothesis that ?-synuclein (?-syn) pathology spreads from gut to brain, via the vagus nerve. Here, we test Braak?s hypothesis by assessing ?-synucleinopathy in the brain in a novel gut-to-brain ?-syn transmission mouse model, where pathological ?-syn preformed fibrils (PFF) were injected into the duodenal and pyloric muscularis layer. Spread of pathologic ?-syn in brain, as assessed by phosphorylation of serine 129 of ?-syn, was observed first in the dorsal motor nucleus, then in caudal portions of the hindbrain including the locus coeruleus, and much later in basolateral amygdala, dorsal raphe nucleus, and the substantia nigra pars compacta. Moreover, loss of dopaminergic neurons, motor and non-motor symptoms were observed in a similar temporal manner. Truncal vagotomy and ?-syn deficiency prevented the gut-to-brain spread of ?- synucleinopathy and associated neurodegeneration and behavioral deficits. This study implicates the Braak hypothesis in the etiology of idiopathic PD.

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Neurodegenerative diseases characterized by aberrant aggregates of the ?-synuclein (?-syn) are collectively referred to as synucleinopathies, and constitute the second most common form of neurodegenerative dementias. Dementia associated with synucleinopathies results from the loss of connectivity within the cognitive circuits, either through cell death or loss of functional connectivity. The work of Braak et al. has further suggested that the neuronal connectivity within this circuit may underlie the path of disease progression and circuit dysfunction associated with Parkinson?s disease (PD) and potentially other synucleinopathies including dementia with Lewy bodies (DLB). The Braak hypothesis posits that ?-syn pathology spreads in a stereotyped fashion from the gastrointestinal tract via the vagus nerve or the olfactory epithelium to the ventral midbrain where it selectively kills dopamine (DA) neurons of the substantia nigra pars compacta (SNc). This hypothesized spread of ?-syn pathology is based on the pattern of Lewy body (LB) pathology observed in post-mortem human brain. In early stages of PD, LB pathology is most often confined to the olfactory bulb or in the intermediate reticular zone (IZ) and dorsal motor nucleus of the vagus (DMV) in the medulla. It is only later during disease progression that LB pathology is observed in the midbrain, affecting the SNc and other regions. The progressive spread of LB is consistent with established synaptic connectivity between hindbrain and midbrain neurons and, based on this pattern, is likely transmitted in a retrograde manner from dendrite to axon. Although the pattern of spread is consistent with retrograde transmission, LB pathology is not observed in all synaptically connected regions. Growing evidence supports that fibril forms of ?-syn, the principal component of LB, can be transmitted from cell to cell in a prion-like manner. Once taken up by a neuron through receptor-mediated endocytosis, ?-syn fibrils can act as a template for the aggregation of endogenous ?-syn protein. The majority of ?-syn in fibrils and in LBs is phosphorylated on serine 129 (pSer129-?-syn). It is not well established if all neuron bearing pSer129-?-syn will eventually form LBs or the effect of pSer129-?-syn accumulation has on synaptic efficacy or connectivity. It has been shown recently that recombinant synthesized ?-syn can be aggregated in vitro to form fibrils similar in structure to those found in vivo. These pre-formed fibrils (PFF) can spread in prion-like manner both in in vitro neuronal cultures as well as in vivo when injected into the mouse brain, forming pSer129-?-syn-positive LB-like inclusions. Injection of PFF into the striatum (STR) of mice results in pSer129-?-syn accumulation and cell death of SNc DA neurons, consistent with retrograde transmission and long-range transport of pathogenic ?-syn. Importantly, both the accumulation and spread of pSer129-?-syn requires endogenous ?-syn, strongly supporting a prion-like templating mechanism. Despite the power of PFF as a model to understand the spread of ?-syn-related pathology, current protocols using PFF fail to reconstitute the spreading observed in humans described by Braak and colleagues. While injection into the STR does lead to pSer129-?-syn spread to SNc DA neurons, there is rarely LB pathology observed in the STR, making this an inaccurate mimic of PD progression. Furthermore, SNc pathology from striatal injection of PFF could reflect an anterograde or retrograde process, as both afferent and efferent connectivity exists between the SNc and STR. Recently, a study was performed where PFF were injected into the olfactory epithelium, one of Braak?s posited sites of PD?s initiation, and while the spread of pSer129-?-syn pathology was extensive there was no accumulation in the SNc. To address the need for a model that recapitulates the features of PD and captures the spread of ?-syn as monitored by pSer129-?-syn, we developed a method where PFF are injected into the muscularis layer of the pylorus and duodenum, mimicking the spread of pSer129-?-syn accumulation observed in Parkinson?s disease. The pSer129-?-syn pathology spreads as Braak proposed, being observed first in the DMV. Later pSer129-?-syn spreads to caudal portions of the hindbrain including the locus coeruleus (LC) and later to the basolateral amygdala (BLA), dorsal raphe nucleus (DRN), and SNc. Truncal vagotomy (TV) prevents the spread of pathologic ?-syn to the brain. In addition, no transmission is observed in ?-syn knockout (SNCA?/?) mice. These observations are consistent with the seeding and misfolding of endogenous ?-syn leading to retrograde, polysynaptic spreading of pathologic ?-syn from the gut via the vagus nerve to the SNc and beyond, mimicking with some accuracy what is seen in clinical synucleinopathies like PD and DLB.

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