Objective: The purpose of this study is to analyze the effect of ATP13A2/PARK9-mediated a-syn secretion on a-syn spreading in mice.

Background: Recent studies with cell culture models, mouse models and human brains have demonstrated that alpha synuclein (a-syn) pre-formed fibrils (pffs) transfer between neurons and spread in the brains, raising the possibility that Parkinson’s disease (PD) is similar to Prion disease, at least in the process in the propagation of pathological proteins.   We and others have reported that ATP13A2/PARK9, of which deficiency leads to one of the monogenic forms of PD, originally described as Kufor-Rakeb syndrome, is involved in a-syn secretion.  While PARK9 deficiency results in increased a-syn levels, enhanced levels of PARK9 can attenuate a-syn accumulation in cultured neurons.  In order to test PARK9-mediated alternations of a-syn levels in vivo, we plan to investigate whether PARK9 affects a-syn spreading in mouse brains.

Method: To investigate the effect of PARK9 levels on a-syn spreading in brains, we inoculated 2.5 ug of mouse pffs into the right striatum of Atp13a2-decicitnt mice, and three months after the inoculations, after euthanized and fixed, we stained the sections with phosphor-a-syn specific antibodies.  In order to analyze the effect of increased levels of PARK9, we injected PARK9-expressing lentivirus one week before pff inoculation at the same right side of striatum.

Results: We did not observe any difference between Atp13a2-decicitnt and wild-type mice in terms of a-syn spreading, while PARK9 overexpression lead to a decrease in a-syn spreading.  Instead, pffs tended to locarize in the area where pffs were inoculated, suggesting the possibility of enhanced PARK9-mediated a-syn secretion from soma, which contributed to a reduction of pffs available for axonal transport to synaptic terminals.

Conclusion: Our results demonstrate that PARK9 levels alter a-syn spreading in the brains, highlighting a close but complex linkage between protein secretion and transmission systems, and providing a novel target for haulting pathological progression of not only Kufor-Rakeb syndrome but also of PD and related synucleinopaties.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/the-effect-of-atp13a2-park9-levels-on-a-syn-spreading-in-mice-brains/