Dataset Information

Transneuronal Propagation of Pathologic ?-Synuclein from the Gut to the Brain Models Parkinson's Disease.

ABSTRACT: Analysis of human pathology led Braak to postulate that ?-synuclein (?-syn) pathology could spread from the gut to brain via the vagus nerve. Here, we test this postulate by assessing ?-synucleinopathy in the brain in a novel gut-to-brain ?-syn transmission mouse model, where pathological ?-syn preformed fibrils 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 and 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 supports the Braak hypothesis in the etiology of idiopathic Parkinson's disease (PD).

SUBMITTER: Kim S

PROVIDER: S-EPMC6706297 | biostudies-literature | 2019 Aug

REPOSITORIES: biostudies-literature

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Publications

Transneuronal Propagation of Pathologic α-Synuclein from the Gut to the Brain Models Parkinson's Disease.

Kim Sangjune S Kwon Seung-Hwan SH Kam Tae-In TI Panicker Nikhil N Karuppagounder Senthilkumar S SS Lee Saebom S Lee Jun Hee JH Kim Wonjoong Richard WR Kook Minjee M Foss Catherine A CA Shen Chentian C Lee Hojae H Kulkarni Subhash S Pasricha Pankaj J PJ Lee Gabsang G Pomper Martin G MG Dawson Valina L VL Dawson Ted M TM Ko Han Seok HS

Neuron 20190626 4

Analysis of human pathology led Braak to postulate that α-synuclein (α-syn) pathology could spread from the gut to brain via the vagus nerve. Here, we test this postulate by assessing α-synucleinopathy in the brain in a novel gut-to-brain α-syn transmission mouse model, where pathological α-syn preformed fibrils were injected into the duodenal and pyloric muscularis layer. Spread of pathologic α-syn in brain, as assessed by phosphorylation of serine 129 of α-syn, was observed first in the dorsal ...[more]

PMID: 31255487

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Project description:The aberrant accumulation of alpha-synuclein (?-syn) is believed to contribute to the onset and pathogenesis of Parkinson's disease (PD). The autophagy-lysosome pathway (ALP) is responsible for the high capacity clearance of ?-syn. ALP dysfunction is documented in PD and pre-clinical evidence suggests that inhibiting the ALP promotes the pathological accumulation of ?-syn. We previously identified the pathological accumulation of ?-syn in the brains of mice deficient for the soluble lysosomal enzyme alpha-Galactosidase A (?-Gal A), a member of the glycosphingolipid metabolism pathway. In the present study, we quantified ?-Gal A activity and levels of its glycosphingolipid metabolites in postmortem temporal cortex specimens from control individuals and in PD individuals staged with respect to ?-syn containing Lewy body pathology. In late-state PD temporal cortex we observed significant decreases in ?-Gal A activity and the 46kDa "active" species of ?-Gal A as determined respectively by fluorometric activity assay and western blot analysis. These decreases in ?-Gal A activity/levels correlated significantly with increased ?-syn phosphorylated at serine 129 (p129S-?-syn) that was maximal in late-stage PD temporal cortex. Mass spectrometric analysis of 29 different isoforms of globotriaosylceramide (Gb3), a substrate of ?-Gal A indicated no significant differences with respect to different stages of PD temporal cortex. However, significant correlations were observed between increased levels of several Gb3 isoforms and with decreased ?-Gal A activity and/or increased p129S-?-syn. Deacylated Gb3 (globotriaosylsphingosine or lyso-Gb3) was also analyzed in PD brain tissue but was below the limit of detection of 20pmol/g. Analysis of other lysosomal enzymes revealed a significant decrease in activity for the lysosomal aspartic acid protease cathepsin D but not for glucocerebrosidase (GCase) or cathepsin B in late-stage PD temporal cortex. However, a significant correlation was observed between decreasing GCase activity and increasing p129S-?-syn. Together our findings indicate ?-Gal A deficiency in late-stage PD brain that correlates significantly with the pathological accumulation of ?-syn, and further suggest the potential for ?-Gal A and its glycosphingolipid substrates as putative biomarkers for PD.

Dataset Information

Transneuronal Propagation of Pathologic ?-Synuclein from the Gut to the Brain Models Parkinson's Disease.

Publications

Transneuronal Propagation of Pathologic α-Synuclein from the Gut to the Brain Models Parkinson's Disease.

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