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Hembach, S. ; Schmidt, S. ; Orschmann, T. ; Burtscher, I. ; Lickert, H. ; Giesert, F. ; Weisenhorn, D.M. ; Wurst, W.

Engrailed 1 deficiency induces changes in ciliogenesis during human neuronal differentiation.

Neurobiol. Dis. 194:106474 (2024)
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A key pathological feature of Parkinson's Disease (PD) is the progressive degeneration of dopaminergic neurons (DAns) in the substantia nigra pars compacta. Considering the major role of EN1 in the development and maintenance of these DAns and the implications from En1 mouse models, it is highly interesting to study the molecular and protective effect of EN1 also in a human cellular model. Therefore, we generated EN1 knock-out (ko) human induced pluripotent stem cell (hiPSCs) lines and analyzed these during neuronal differentiation. Although the EN1 ko didn't interfere with neuronal differentiation and generation of tyrosine hydroxylase positive (TH+) neurons per se, the neurons exhibited shorter neurites. Furthermore, mitochondrial respiration, as well as mitochondrial complex I abundance was significantly reduced in fully differentiated neurons. To understand the implications of an EN1 ko during differentiation, we performed a transcriptome analysis of human neuronal precursor cells (hNPCs) which unveiled alterations in cilia-associated pathways. Further analysis of ciliary morphology revealed an elongation of primary cilia in EN1-deficient hNPCs. Besides, also Wnt signaling pathways were severely affected. Upon stimulating hNPCs with Wnt which drastically increased EN1 expression in WT lines, the phenotypes concerning mitochondrial function and cilia were exacerbated in EN1 ko hNPCs. They failed to enhance the expression of the complex I subunits NDUFS1 and 3, and now displayed a reduced mitochondrial respiration. Furthermore, Wnt stimulation decreased ciliogenesis in EN1 ko hNPCs but increased ciliary length even further. This further highlights the relevance of primary cilia next to mitochondria for the functionality and correct maintenance of human DAns and provides new possibilities to establish neuroprotective therapies for PD.
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Publication type Article: Journal article
Document type Scientific Article
Keywords Engrailed 1 ; Wnt Signaling ; Complex I ; Dopaminergic Neuron ; Induced Pluripotent Stem Cells ; Mitochondrial Respiration ; Primary Cilia; Midbrain Dopaminergic-neurons; Mitochondrial Dysfunction; Parkinsons-disease; Signaling Pathway; Containing Genes; Stem-cells; Mouse; Degeneration; Mice; Localization
Language english
Publication Year 2024
HGF-reported in Year 2024
ISSN (print) / ISBN 0969-9961
e-ISSN 1095-953X
Journal Neurobiology of Disease
Quellenangaben Volume: 194, Issue: , Pages: , Article Number: 106474 Supplement: ,
Publisher Elsevier
Publishing Place 525 B St, Ste 1900, San Diego, Ca 92101-4495 Usa
Reviewing status Peer reviewed
Institute(s) Institute of Developmental Genetics (IDG)
Institute of Diabetes and Regeneration Research (IDR)
POF-Topic(s) 30204 - Cell Programming and Repair
30201 - Metabolic Health
Research field(s) Genetics and Epidemiology
Helmholtz Diabetes Center
PSP Element(s) G-500500-001
G-500591-001
G-502300-001
Grants Helmholtz Association
Bavarian State Ministry of Science and the Arts within the initial phase of the German Center for Mental Health (Deutsches Zentrum fur Psychische Gesundheit
Federal Ministry of Education and Research (BMBF)
DOI 10.1016/j.nbd.2024.106474
WOS ID 001224446700001
Scopus ID 85189026782
PubMed ID 38518837
Erfassungsdatum 2024-05-13
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