? Project 1 A growing body of evidence suggests Parkinson?s disease (PD) pathogenesis initiates from the gastrointestinal tract through enteric neurons in the autonomic nervous system and spreads to the central nervous system (CNS), yet little information is known about how the enteric nervous system (ENS) serves as a conduit for pathologic ?-synuclein (?-syn) transmission to the CNS. Our study is based on strong preliminary data, in which we show that pathological ?-syn transmits from the ENS to CNS neurons in mice. In addition, it is based on our recent findings that c-Abl activation and phosphorylation of ?-syn at tyrosine 39 (pY39 ?-syn) contributes to the death of DA neurons due to ?-syn aggregation in vivo. Our application will pinpoint the anatomical components and pathways in the process of ?-syn transmission by using a novel gut to brain transmission mouse model of PD. In addition, it will test the effects of c-Abl activation and phosphorylation of ?-syn at Y39 by using c-Abl knockout (KO) mice and Y39F ?-syn knockin (KI) mice on ?-syn transmission from the gut to the brain.
In Aim1, we aim to validate and optimize the novel gut to brain ?-syn transmission mouse model of PD by examining the time course and magnitude of the ENS and CNS ?-synucleinopathy in various brain regions.
In Aim 2, we will comprehensively map the potential route responsible for ascending ?-syn from the ENS to the CNS by generating conditional KO of ?-syn, which is required for ?-syn transmission, in a pathway-specific manner in the vagus nerve in the gut-brain ?-syn PFF PD model. To explore this, we will generate 1) ?-synflx/flx/Tbx1-Cre mice for vagal sensory afferent depletion of ?-syn, 2) ?-synflx/flx/ChAT-IRES-Cre mice for vagal motor efferent depletion of ?-syn, and 3) ?-synflx/flx/Nestin-Cre for a pan-neuronal depletion of ?- syn as a control. We will monitor the CNS ?-synucleinopathy induced by the gastrointestinal ?-syn PFF injection in these ?-syn KO mice.
In Aim 3, we will investigate the role of c-Abl activation in the vagal nerves on ?-syn transmission from the ENS to the CNS. To this end, we will generate 1) c-Ablflx/flx/Tbx1-Cre mice for the vagal sensory afferents depletion of c-Abl, 2) c-Ablflx/flx/ChAT-IRES-Cre mice for vagal motor efferent depletion of c-Abl, and 3) c-Ablflx/flx/Nestin-Cre for a pan-neuronal depletion of c-Abl as a control. We will monitor the CNS ?-synucleinopathy induced by the gastrointestinal PFF injection in these c-Abl KO mice. In addition, in Aim 3, we will explore if molecules in the c-Abl pathway are elevated in serum L1Cam exosomes of the gut-brain ?-syn PFF model in a time-dependent manner. Lastly, in Aim 4, we will explore the role of pY39 ?-syn on the transmission of ?-syn from the ENS to the CNS . To this end, Y39F ?-syn (phospho-deficient) knockin (KI) mice were generated during the last funding cycle. We will monitor the CNS ?-synucleinopathy induced by the gastrointestinal or striatal PFF injection in the Y39 KI mice. This investigation will broaden our understanding of the pathogenic mechanism of PD and lead to new therapeutic interventions for PD. Additionally, this work will provide a new animal model of ?-syn transmission that can be used for testing the effect of a variety of disease-modifying therapeutics in PD.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Specialized Center (P50)
Project #
2P50NS038377-21
Application #
9849924
Study Section
Special Emphasis Panel (ZNS1)
Project Start
Project End
Budget Start
2019-08-01
Budget End
2020-07-31
Support Year
21
Fiscal Year
2019
Total Cost
Indirect Cost
Name
Johns Hopkins University
Department
Type
DUNS #
001910777
City
Baltimore
State
MD
Country
United States
Zip Code
21205
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Kam, Tae-In; Mao, Xiaobo; Park, Hyejin et al. (2018) Poly(ADP-ribose) drives pathologic ?-synuclein neurodegeneration in Parkinson's disease. Science 362:
Sathe, Gajanan; Na, Chan Hyun; Renuse, Santosh et al. (2018) Phosphotyrosine profiling of human cerebrospinal fluid. Clin Proteomics 15:29
Guerreiro, Rita; Ross, Owen A; Kun-Rodrigues, Celia et al. (2018) Investigating the genetic architecture of dementia with Lewy bodies: a two-stage genome-wide association study. Lancet Neurol 17:64-74
Hinkle, Jared T; Perepezko, Kate; Bakker, Catherine C et al. (2018) Domain-specific cognitive impairment in non-demented Parkinson's disease psychosis. Int J Geriatr Psychiatry 33:e131-e139
Hinkle, Jared T; Perepezko, Kate; Mills, Kelly A et al. (2018) Dopamine transporter availability reflects gastrointestinal dysautonomia in early Parkinson disease. Parkinsonism Relat Disord 55:8-14
Kim, Donghoon; Hwang, Heehong; Choi, Seulah et al. (2018) D409H GBA1 mutation accelerates the progression of pathology in A53T ?-synuclein transgenic mouse model. Acta Neuropathol Commun 6:32
Kim, Sangjune; Yun, Seung Pil; Lee, Saebom et al. (2018) GBA1 deficiency negatively affects physiological ?-synuclein tetramers and related multimers. Proc Natl Acad Sci U S A 115:798-803
Kim, Donghoon; Yoo, Je Min; Hwang, Heehong et al. (2018) Graphene quantum dots prevent ?-synucleinopathy in Parkinson's disease. Nat Nanotechnol :
Hinkle, Jared T; Perepezko, Kate; Mari, Zoltan et al. (2018) Perceived Treatment Status of Fluctuations in Parkinson Disease Impacts Suicidality. Am J Geriatr Psychiatry 26:700-710

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