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.
Letters: Rapid online correspondence
REQUIREMENTS
If you are uploading a letter concerning an article:
You must have updated your disclosures within six months: http://submit.neurology.org
Your co-authors must send a completed Publishing Agreement Form to Neurology Staff (not necessary for the lead/corresponding author as the form below will suffice) before you upload your comment.
If you are responding to a comment that was written about an article you originally authored:
You (and co-authors) do not need to fill out forms or check disclosures as author forms are still valid
and apply to letter.
Submission specifications:
- Submissions must be < 200 words with < 5 references. Reference 1 must be the article on which you are commenting.
- Submissions should not have more than 5 authors. (Exception: original author replies can include all original authors of the article)
- Submit only on articles published within 6 months of issue date.
- Do not be redundant. Read any comments already posted on the article prior to submission.
- Submitted comments are subject to editing and editor review prior to posting.
