TY - JOUR
T1 - Parallel neurodegenerative phenotypes in sporadic Parkinson's disease fibroblasts and midbrain dopamine neurons
AU - Corenblum, M. J.
AU - McRobbie-Johnson, A.
AU - Carruth, E.
AU - Bernard, K.
AU - Luo, M.
AU - Mandarino, L. J.
AU - Peterson, S.
AU - Sans-Fuentes, M. A.
AU - Billheimer, D.
AU - Maley, T.
AU - Eggers, E. D.
AU - Madhavan, L.
N1 - Funding Information:
We thank Dr Helena Morrison and Dr Wayne Willis for their expert input on the mitochondrial ATPIF1 and seahorse data. We also acknowledge Drs Tony Day and Paula Tonino for their assistance with the transmission electron microscopy work, which was performed in the Imaging Cores-Electron at the University of Arizona Research, Innovation, and Impact Core Facilities. The cell lines used in this study were partially obtained from the Parkinson’s Progression Markers Initiative (PPMI) [www.ppmi-info.org]. PPMI, a public private partnership, is funded by the Michael J. Fox Foundation for Parkinson’s Research and corporate sponsors [https://www.ppmi-info.org/about ppmi/who-we-are/study-sponsors]. The study was supported by a Michael J Fox Foundation Grant (MJFF 18366 ), Tech Launch Arizona ( MDH-21 ), and UA intramural funds to LM, and National Eye Institute Grant R01-EY-026027 and NSF - 1552184 to EE.
Funding Information:
We thank Dr Helena Morrison and Dr Wayne Willis for their expert input on the mitochondrial ATPIF1 and seahorse data. We also acknowledge Drs Tony Day and Paula Tonino for their assistance with the transmission electron microscopy work, which was performed in the Imaging Cores-Electron at the University of Arizona Research, Innovation, and Impact Core Facilities. The cell lines used in this study were partially obtained from the Parkinson's Progression Markers Initiative (PPMI) [www.ppmi-info.org]. PPMI, a public private partnership, is funded by the Michael J. Fox Foundation for Parkinson's Research and corporate sponsors [https://www.ppmi-info.org/about ppmi/who-we-are/study-sponsors]. The study was supported by a Michael J Fox Foundation Grant (MJFF 18366), Tech Launch Arizona (MDH-21), and UA intramural funds to LM, and National Eye Institute Grant R01-EY-026027 and NSF-1552184 to EE. MJC – Experimental design, Collection and assembly of data, Data analysis and Interpretation, Manuscript writing. AMJ – Collection and assembly of data, Data analysis and Interpretation, Manuscript writing. EC – Collection and assembly of data, Data analysis. TM – Collection, assembly and analysis of electrophysiology data, Manuscript writing. EE – Conception and design of electrophysiology experiments, Data analysis and resources support, Manuscript editing. KB – Collection, assembly, data analysis of ATPIF1 data, Manuscript editing. ML – Experimental design, execution, and data analysis support for Seahorse experiments. LJM – Experimental design, data interpretation and resources support for Seahorse experiments, Manuscript editing. SP – Statistical data analysis and interpretation, Manuscript editing. MSF– Statistical data analysis and interpretation, Manuscript editing. DB – Statistical data analysis and interpretation, Manuscript editing. LM – Overall conception and design of the study, Collection and assembly of data, Data analysis and Interpretation, Manuscript writing, Financial support, Final approval of manuscript. 1) Supplementary Figures 1, 2, 3 & 4. 2) Supplementary Methods.
Publisher Copyright:
© 2023 The Authors
PY - 2023/10
Y1 - 2023/10
N2 - Understanding the mechanisms causing Parkinson's disease (PD) is vital to the development of much needed early diagnostics and therapeutics for this debilitating condition. Here, we report cellular and molecular alterations in skin fibroblasts of late-onset sporadic PD subjects, that were recapitulated in matched induced pluripotent stem cell (iPSC)-derived midbrain dopamine (DA) neurons, reprogrammed from the same fibroblasts. Specific changes in growth, morphology, reactive oxygen species levels, mitochondrial function, and autophagy, were seen in both the PD fibroblasts and DA neurons, as compared to their respective controls. Additionally, significant alterations in alpha synuclein expression and electrical activity were also noted in the PD DA neurons. Interestingly, although the fibroblast and neuronal phenotypes were similar to each other, they differed in their nature and scale. Furthermore, statistical analysis revealed potential novel associations between various clinical measures of the PD subjects and the different fibroblast and neuronal data. In essence, these findings encapsulate spontaneous, in-tandem, disease-related phenotypes in both sporadic PD fibroblasts and iPSC-based DA neurons, from the same patient, and generates an innovative model to investigate PD mechanisms with a view towards rational disease stratification and precision treatments.
AB - Understanding the mechanisms causing Parkinson's disease (PD) is vital to the development of much needed early diagnostics and therapeutics for this debilitating condition. Here, we report cellular and molecular alterations in skin fibroblasts of late-onset sporadic PD subjects, that were recapitulated in matched induced pluripotent stem cell (iPSC)-derived midbrain dopamine (DA) neurons, reprogrammed from the same fibroblasts. Specific changes in growth, morphology, reactive oxygen species levels, mitochondrial function, and autophagy, were seen in both the PD fibroblasts and DA neurons, as compared to their respective controls. Additionally, significant alterations in alpha synuclein expression and electrical activity were also noted in the PD DA neurons. Interestingly, although the fibroblast and neuronal phenotypes were similar to each other, they differed in their nature and scale. Furthermore, statistical analysis revealed potential novel associations between various clinical measures of the PD subjects and the different fibroblast and neuronal data. In essence, these findings encapsulate spontaneous, in-tandem, disease-related phenotypes in both sporadic PD fibroblasts and iPSC-based DA neurons, from the same patient, and generates an innovative model to investigate PD mechanisms with a view towards rational disease stratification and precision treatments.
KW - Aging
KW - Human Induced Pluripotent Stem Cells
KW - Midbrain Dopamine Neurons
KW - Mitochondrial Dysfunction
KW - Parkinson's disease
KW - Skin fibroblasts
UR - http://www.scopus.com/inward/record.url?scp=85165461561&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85165461561&partnerID=8YFLogxK
U2 - 10.1016/j.pneurobio.2023.102501
DO - 10.1016/j.pneurobio.2023.102501
M3 - Article
C2 - 37451330
AN - SCOPUS:85165461561
SN - 0301-0082
VL - 229
JO - Progress in Neurobiology
JF - Progress in Neurobiology
M1 - 102501
ER -