scholarly journals Quantitative Proteomic Analysis of Primitive Neural Stem Cells from LRRK2 G2019S-Associated Parkinson’s Disease Patient-Derived iPSCs

Life ◽  
2020 ◽  
Vol 10 (12) ◽  
pp. 331
Author(s):  
Hyuna Sim ◽  
Ji-Hye Seo ◽  
Jumi Kim ◽  
Minyoung Oh ◽  
Joo-Eun Lee ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Stem Cells ◽  
Parkinson's Disease ◽  
Proteomic Analysis ◽  
Disease Patient ◽  
Experimental System ◽  
Model System ◽  
Neural Cells ◽  
Quantitative Proteomic Analysis ◽  
G2019s Mutation

Parkinson’s disease (PD) is a common neurodegenerative disease, causing movement defects. The incidence of PD is constantly increasing and this disease is still incurable. Thus, understanding PD pathophysiology would be pivotal for the development of PD therapy, and various PD models have thus been already developed. Through recent advances in reprogramming techniques, a primitive neural stem cell (pNSC) derived from PD patient induced pluripotent stem cells (iPSCs) could be potentially used as a reproducible and reliable experimental system to analyze the effect of the leucine-rich repeat kinase 2 G2019S mutation (LK2GS) in neural cells. Here, we investigated the advantages of such a model system through quantitative proteomic analysis of pNSCs from normal control iPSCs and familial PD patient iPSCs harboring LK2GS. We confirmed that the expression of molecules known to be involved in PD pathogenesis, such as oxidative stress-, cell adhesion-, and cytoskeleton-related proteins, were altered in the LK2GS pNSC. In addition, we showed that down-regulation of Ku80, which was found in the proteomic analysis with LK2GS pNSCs, resulted in apoptosis induced by DNA damage response. Taken together, we suggest that pNSCs from PD iPSCs could provide a reliable and useful model system to study PD. Moreover, the highly expandable pNSC is suitable for multi-omics approaches to understand PD pathologies and discover therapeutic targets for PD.

scholarly journals In vivo phenotyping of Parkinson-specific stem cells reveals increased a-Synuclein levels but no spreading

2017 ◽  
Author(s):  
Kathrin Hemmer ◽  
Lisa M. Smits ◽  
Silvia Bolognin ◽  
Jens C. Schwamborn
Keyword(s):  
Parkinson’S Disease ◽  
Stem Cells ◽  
Parkinson's Disease ◽  
Mouse Brain ◽  
Disease Modeling ◽  
Disease Patient ◽  
Alpha Synuclein ◽  
Patient Specific ◽  
Species Barrier

AbstractParkinson′s disease is a progressive age-associated neurological disorder. One of the major neuropathological hallmarks of Parkinson’s disease is the appearance of protein aggregates, mainly consisting of the protein alpha-Synuclein. These aggregates have been described both in genetic as well as idiopathic forms of the disease. Currently, Parkinson’s disease patient-specific induced pluripotent stem cells (iPSCs) are mainly used for in vitro disease modeling or for experimental cell replacement approaches. Here, we demonstrate that these cells can be used for in vivo disease modeling. We show that Parkinson’s disease patient-specific, iPSC-derived neurons carrying the LRRK2-G2019S mutation show an upregulation of alpha-Synuclein after transplantation in the mouse brain. However, further investigations indicate that the increased human alpha-Synuclein levels fail to induce spreading or aggregation in the mouse brain. We therefore conclude that grafting of these cells into the mouse brain is suitable for cell autonomous in vivo disease modeling but has strong limitations beyond that. Furthermore, our results support the hypothesis that there might be a species barrier between human to mouse concerning alpha-Synuclein spreading.

scholarly journals Mitochondrial clearance and maturation of autophagosomes are compromised in LRRK2 G2019S familial Parkinson’s disease patient fibroblasts

2019 ◽  
Vol 28 (19) ◽  
pp. 3232-3243 ◽  
Author(s):  
Joanna A Korecka ◽  
Ria Thomas ◽  
Dan P Christensen ◽  
Anthony J Hinrich ◽  
Eliza J Ferrari ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Human Fibroblasts ◽  
Disease Patient ◽  
G2019s Mutation ◽  
Mechanistic Analysis ◽  
Lrrk2 G2019s ◽  
Diagnostic Approaches ◽  
Mutant Lrrk2 ◽  
Familial Parkinson’S Disease

AbstractThis study utilized human fibroblasts as a preclinical discovery and diagnostic platform for identification of cell biological signatures specific for the LRRK2 G2019S mutation producing Parkinson’s disease (PD). Using live cell imaging with a pH-sensitive Rosella biosensor probe reflecting lysosomal breakdown of mitochondria, mitophagy rates were found to be decreased in fibroblasts carrying the LRRK2 G2019S mutation compared to cells isolated from healthy subject (HS) controls. The mutant LRRK2 increased kinase activity was reduced by pharmacological inhibition and targeted antisense oligonucleotide treatment, which normalized mitophagy rates in the G2019S cells and also increased mitophagy levels in HS cells. Detailed mechanistic analysis showed a reduction of mature autophagosomes in LRRK2 G2019S fibroblasts, which was rescued by LRRK2 specific kinase inhibition. These findings demonstrate an important role for LRRK2 protein in regulation of mitochondrial clearance by the lysosomes, which is hampered in PD with the G2019S mutation. The current results are relevant for cell phenotypic diagnostic approaches and potentially for stratification of PD patients for targeted therapy.

scholarly journals Proteomic analysis of Parkinson’s disease patient cohorts show similarities in mechanism to Alzheimer’s disease

2021 ◽  
Vol 17 (S5) ◽  
Author(s):  
Laura M. Winchester ◽  
Michael Lawton ◽  
Imelda S. Barber ◽  
Samuel Evetts ◽  
Brent Ryan ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Parkinson’S Disease ◽  
Alzheimer's Disease ◽  
Parkinson's Disease ◽  
Proteomic Analysis ◽  
Disease Patient
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