Parallel Neurodegenerative Phenotypes in Sporadic Parkinson’s Disease Fibroblasts and Midbrain Dopamine Neurons

Abstract

Understanding the mechanisms causing Parkinsons 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 also differed in their nature and scale. Furthermore, statistical analysis revealed 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.

Impaired Mitochondrial Respiration in REM‐Sleep Behavior Disorder: A Biomarker of Parkinson's Disease?

“…Similarly, Ambrosi and colleagues 22 observed reduced maximal respiration and rotenonesensitive respiration levels in the same patients. Corenblum and colleagues 23 recently confirmed concurrent respiratory dysfunction and network fragmentation in fibroblasts from late-onset sporadic PD and induced pluripotent stem cells (iPSC)-based dopamingeric neurons from the same patients. Although some variations in mitochondrial respiration were noted between the two cell types, possibly because of fibroblasts' compensatory capacity for mitochondrial issues, this study suggests that peripheral tissue dysfunction may be linked to brain abnormalities in patients.…”