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Neurology Genetics
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December 2021; 7 (6) ArticleOpen Access

CSF MicroRNAs Reveal Impairment of Angiogenesis and Autophagy in Parkinson Disease

Alan J. Fowler, Jaeil Ahn, Michaeline Hebron, Timothy Chiu, Reem Ayoub, Sanjana Mulki, View ORCID ProfileHabtom Ressom, View ORCID ProfileYasar Torres-Yaghi, Barbara Wilmarth, Fernando L. Pagan, Charbel Moussa
First published November 12, 2021, DOI: https://doi.org/10.1212/NXG.0000000000000633
Alan J. Fowler
From the Translational Neurotherapeutics Program (A.J.F., M.H., T.C., R.A., S.M., B.W., F.L.P., C.M.), Department of Neurology; Interdisciplinary Program in Neuroscience (A.J.F.); Department of Biostatistics, Bioinformatics, and Biomathematics (J.A.); Department of Oncology (H.R.), Lombardi Comprehensive Cancer Center, Georgetown University Medical Center; and Movement Disorders Clinic (Y.T.Y., B.W., F.L.P., C.M.), Department of Neurology, MedStar Georgetown University Hospital, Washington, DC.
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  • For correspondence: ajf115@georgetown.edu
Jaeil Ahn
From the Translational Neurotherapeutics Program (A.J.F., M.H., T.C., R.A., S.M., B.W., F.L.P., C.M.), Department of Neurology; Interdisciplinary Program in Neuroscience (A.J.F.); Department of Biostatistics, Bioinformatics, and Biomathematics (J.A.); Department of Oncology (H.R.), Lombardi Comprehensive Cancer Center, Georgetown University Medical Center; and Movement Disorders Clinic (Y.T.Y., B.W., F.L.P., C.M.), Department of Neurology, MedStar Georgetown University Hospital, Washington, DC.
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  • For correspondence: ja1030@georgetown.edu
Michaeline Hebron
From the Translational Neurotherapeutics Program (A.J.F., M.H., T.C., R.A., S.M., B.W., F.L.P., C.M.), Department of Neurology; Interdisciplinary Program in Neuroscience (A.J.F.); Department of Biostatistics, Bioinformatics, and Biomathematics (J.A.); Department of Oncology (H.R.), Lombardi Comprehensive Cancer Center, Georgetown University Medical Center; and Movement Disorders Clinic (Y.T.Y., B.W., F.L.P., C.M.), Department of Neurology, MedStar Georgetown University Hospital, Washington, DC.
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  • For correspondence: mlh88@georgetown.edu
Timothy Chiu
From the Translational Neurotherapeutics Program (A.J.F., M.H., T.C., R.A., S.M., B.W., F.L.P., C.M.), Department of Neurology; Interdisciplinary Program in Neuroscience (A.J.F.); Department of Biostatistics, Bioinformatics, and Biomathematics (J.A.); Department of Oncology (H.R.), Lombardi Comprehensive Cancer Center, Georgetown University Medical Center; and Movement Disorders Clinic (Y.T.Y., B.W., F.L.P., C.M.), Department of Neurology, MedStar Georgetown University Hospital, Washington, DC.
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  • For correspondence: tlc76@georgetown.edu
Reem Ayoub
From the Translational Neurotherapeutics Program (A.J.F., M.H., T.C., R.A., S.M., B.W., F.L.P., C.M.), Department of Neurology; Interdisciplinary Program in Neuroscience (A.J.F.); Department of Biostatistics, Bioinformatics, and Biomathematics (J.A.); Department of Oncology (H.R.), Lombardi Comprehensive Cancer Center, Georgetown University Medical Center; and Movement Disorders Clinic (Y.T.Y., B.W., F.L.P., C.M.), Department of Neurology, MedStar Georgetown University Hospital, Washington, DC.
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  • For correspondence: reemayoub17@gmail.com
Sanjana Mulki
From the Translational Neurotherapeutics Program (A.J.F., M.H., T.C., R.A., S.M., B.W., F.L.P., C.M.), Department of Neurology; Interdisciplinary Program in Neuroscience (A.J.F.); Department of Biostatistics, Bioinformatics, and Biomathematics (J.A.); Department of Oncology (H.R.), Lombardi Comprehensive Cancer Center, Georgetown University Medical Center; and Movement Disorders Clinic (Y.T.Y., B.W., F.L.P., C.M.), Department of Neurology, MedStar Georgetown University Hospital, Washington, DC.
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  • For correspondence: sjm153@georgetown.edu
Habtom Ressom
From the Translational Neurotherapeutics Program (A.J.F., M.H., T.C., R.A., S.M., B.W., F.L.P., C.M.), Department of Neurology; Interdisciplinary Program in Neuroscience (A.J.F.); Department of Biostatistics, Bioinformatics, and Biomathematics (J.A.); Department of Oncology (H.R.), Lombardi Comprehensive Cancer Center, Georgetown University Medical Center; and Movement Disorders Clinic (Y.T.Y., B.W., F.L.P., C.M.), Department of Neurology, MedStar Georgetown University Hospital, Washington, DC.
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  • ORCID record for Habtom Ressom
  • For correspondence: hwr@georgetown.edu
Yasar Torres-Yaghi
From the Translational Neurotherapeutics Program (A.J.F., M.H., T.C., R.A., S.M., B.W., F.L.P., C.M.), Department of Neurology; Interdisciplinary Program in Neuroscience (A.J.F.); Department of Biostatistics, Bioinformatics, and Biomathematics (J.A.); Department of Oncology (H.R.), Lombardi Comprehensive Cancer Center, Georgetown University Medical Center; and Movement Disorders Clinic (Y.T.Y., B.W., F.L.P., C.M.), Department of Neurology, MedStar Georgetown University Hospital, Washington, DC.
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  • ORCID record for Yasar Torres-Yaghi
  • For correspondence: yasar.torres-yaghi@gunet.georgetown.edu
Barbara Wilmarth
From the Translational Neurotherapeutics Program (A.J.F., M.H., T.C., R.A., S.M., B.W., F.L.P., C.M.), Department of Neurology; Interdisciplinary Program in Neuroscience (A.J.F.); Department of Biostatistics, Bioinformatics, and Biomathematics (J.A.); Department of Oncology (H.R.), Lombardi Comprehensive Cancer Center, Georgetown University Medical Center; and Movement Disorders Clinic (Y.T.Y., B.W., F.L.P., C.M.), Department of Neurology, MedStar Georgetown University Hospital, Washington, DC.
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  • For correspondence: barbara.m.wilmarth@gunet.georgetown.edu
Fernando L. Pagan
From the Translational Neurotherapeutics Program (A.J.F., M.H., T.C., R.A., S.M., B.W., F.L.P., C.M.), Department of Neurology; Interdisciplinary Program in Neuroscience (A.J.F.); Department of Biostatistics, Bioinformatics, and Biomathematics (J.A.); Department of Oncology (H.R.), Lombardi Comprehensive Cancer Center, Georgetown University Medical Center; and Movement Disorders Clinic (Y.T.Y., B.W., F.L.P., C.M.), Department of Neurology, MedStar Georgetown University Hospital, Washington, DC.
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  • For correspondence: fpogan01@gunet.georgetown.edu
Charbel Moussa
From the Translational Neurotherapeutics Program (A.J.F., M.H., T.C., R.A., S.M., B.W., F.L.P., C.M.), Department of Neurology; Interdisciplinary Program in Neuroscience (A.J.F.); Department of Biostatistics, Bioinformatics, and Biomathematics (J.A.); Department of Oncology (H.R.), Lombardi Comprehensive Cancer Center, Georgetown University Medical Center; and Movement Disorders Clinic (Y.T.Y., B.W., F.L.P., C.M.), Department of Neurology, MedStar Georgetown University Hospital, Washington, DC.
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Citation
CSF MicroRNAs Reveal Impairment of Angiogenesis and Autophagy in Parkinson Disease
Alan J. Fowler, Jaeil Ahn, Michaeline Hebron, Timothy Chiu, Reem Ayoub, Sanjana Mulki, Habtom Ressom, Yasar Torres-Yaghi, Barbara Wilmarth, Fernando L. Pagan, Charbel Moussa
Neurol Genet Dec 2021, 7 (6) e633; DOI: 10.1212/NXG.0000000000000633

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Abstract

Background and Objectives We assessed longitudinal changes in CSF microRNAs (miRNAs) in patients with moderately severe Parkinson disease.

Methods We used next-generation whole-genome miRNA sequencing to determine CSF miRNA expression in 75 patients with Parkinson disease after single random ascending doses of nilotinib and longitudinal miRNA expression after daily nilotinib, 150 and 300 mg, vs placebo for 1 year.

Results Significant changes in the expression of miRNAs that control genes and pathways that regulate angiogenesis, autophagy, and the blood-brain-barrier components, primarily collagen, were observed over 1 year, suggesting impairment of these pathways in Parkinson progression in these patients. Different miRNAs that indicate activation of genes associated with autophagy flux and clearance and angiogenesis were significantly altered in the nilotinib, 300 mg vs 150 mg, or placebo group, and these changes correlated with clinical outcomes. No changes were observed in miRNAs after a single dose of nilotinib vs placebo.

Discussion This study suggests vascular and autophagy defects in Parkinson progression. Nilotinib, 300 mg, reverses these effects via alteration of miRNA expression, suggesting epigenomic changes that may underlie long-term disease-modifying effects.

Trial Registration Information Clinical trial registration number: NCT02954978.

Glossary

BBB=
blood-brain barrier;
DDR=
discoidin domain receptor;
DEM=
differentially expressed miRNA;
ECM=
extracellular matrix;
FC=
fold change;
FR=
fold regulation;
GO=
gene ontology;
IC50=
half-maximal inhibitor concentration;
LAMP=
lysosome-associated membrane protein;
MDS-UPDRS=
Movement Disorders Society–Unified Parkinson's Disease Rating Scale;
ME-ANOVA=
mixed-effects analysis of variance;
miRNA=
microRNA;
MMP=
matrix metalloprotease;
MOCA=
Montreal Cognitive Assessment;
TKI=
tyrosine kinase inhibition;
UMI=
Unique Molecular Identifier;
UPDRS=
Unified Parkinson's Disease Rating Scale;
PD=
Parkinson disease;
PDQ39=
Parkinson's Disease Questionnaire 39;
VEGF=
vascular endothelial growth factor

Footnotes

  • Go to Neurology.org/NG for full disclosures. Funding information is provided at the end of the article.

  • The Article Processing Charge was funded by the authors.

  • ↵* These authors contributed equally to bioinformatics and biostatistical analysis of this manuscript.

  • Received April 28, 2021.
  • Accepted in final form August 27, 2021.
  • Copyright © 2021 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.

This is an open access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivatives License 4.0 (CC BY-NC-ND), which permits downloading and sharing the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal.

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