Prion 2015 Oral Abstracts

Abstract

Multiple system atrophy (MSA) and Parkinson's disease are synucleinopathies that are defined by the presence of aggregated and hyperphosphorylated a-synuclein (a-syn) within cells of the central nervous system (CNS). Recent findings suggest that pathological a-syn may spread prion-like within the nervous system. We investigated prion-like propagation of pathological a-syn in Tg(SNCA)1Nbm/J mice that do not express mouse but low levels of human wt a-syn and do not naturally develop any pathology or neurodegenerative disease. We inoculated brain homogenate from 2 patients with MSA, from 2 aged control subjects without neurological disorder, or saline intrastriatally into Tg(SNCA)1Nbm/J mice. Challenged mice were sacrificed at 90, 180, and 270 d post inoculation and were analyzed biochemically and immunohistochemically for pathological a-syn. Brain homogenates from MSA or aged control subjects but not saline triggered progressive accumulation of aggregated a-syn in neurons of inoculated mice. Aggregates of a-syn were hyperphosphorylated and costained for p62 that targets proteins for degradation. Aggregates of pathological a-syn were first observable in the ipsilateral brain hemisphere and over time in the contralateral hemisphere and in more rostral and caudal areas. Our findings show that brain homogenate from MSA patients but not saline induces pathological changes in the CNS of Tg(SNCA) 1Nbm/J mice. Our data support that pathological a-syn may propagate prion-like along neuronal networks. Furthermore, human wt a-syn supports propagation of pathological a-syn. Intriguingly, brain homogenate from aged control subjects without neurological disorder equally induced synucleinopathy in brains of Tg(SNCA)1Nbm/J mice suggesting that aged human brains can contain pathological a-syn.