CSF MicroRNAs Reveal Impairment of Angiogenesis and Autophagy in Parkinson Disease

Abstract

Background and ObjectivesWe assessed longitudinal changes in CSF microRNAs (miRNAs) in patients with moderately severe Parkinson disease.MethodsWe 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.ResultsSignificant 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.DiscussionThis 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 InformationClinical trial registration number: NCT02954978.

Microvascular Changes in Parkinson’s Disease- Focus on the Neurovascular Unit

“…In this study, angiogenesis markers in the CSF were associated with microbleeds and white matter lesions on imaging, suggesting abnormal angiogenesis in PD (Janelidze et al, 2015). Further strengthening these findings, a recent study demonstrated CSF changes in miRNAs regulating pathways of angiogenesis and BBB components in PD patients with moderate disease, implying impairment of these pathways as part of the progression of PD (Fowler et al, 2021).…”

Alteration of Autophagy and Glial Activity in Nilotinib-Treated Huntington’s Disease Patients

“…Importantly, DDR1 activation alters microglial activity [25], whereas deletion or inhibition of DDR1 attenuates neuro-inflammation and improves autophagy, bioenergetics and vesicular transport in the CNS [17,[26][27][28][29]. We previously observed significant alterations in miRNAs that control autophagy and inflammation genes in PD patients treated with nilotinib, which reverses these miRNA levels [53] in agreement with the preclinical effects of nilotinib on the molecular pathways of autophagy and inflammation [21][22][23][29][30][31][32][33]. Nilotinib, 150 mg and 300 mg, led a dose dependent reduction of neurotoxic proteins, including tau in PD [22] and amyloid in AD [41] patients.…”

“…Nilotinib is a potent inhibitor of DDR1 (IC50 1 nM) [16][17][18][19][20]53] and it adequately enters the brain in PD (up to 4.12 nM) [21][22][23]34] and AD (up to 4.7 nM) [41] patients to inhibit DDR1. Importantly, DDR1 activation alters microglial activity [25], whereas deletion or inhibition of DDR1 attenuates neuro-inflammation and improves autophagy, bioenergetics and vesicular transport in the CNS [17,[26][27][28][29].…”

Nilotinib modulates LPS-induced cognitive impairment and neuroinflammatory responses by regulating P38/STAT3 signaling

“…Moreover, whole-genome sequencing of miRNAs in the CSF of PD patients treated with nilotinib (150 mg, 300 mg, p.o. for 12 months) demonstrated that nilotinib reduces factors associated with BBB degradation and restores autophagy-linked factors, markers of neuroinflammation, and micro-environmental markers of angiogenesis [ 49 ]. Taken together, these findings indicate that nilotinib blocks DDR1 activity and downregulates AD and PD pathology.…”