Explore chapters and articles related to this topic
Stem Cells for Parkinson’s Disease
Published in Deepak A. Lamba, Patient-Specific Stem Cells, 2017
Leucine-rich repeat kinase 2 (LRRK2) is the most common form of familial PD (5). The most common mutation is G2019S, found in the mixed lineage kinase-like domain, which results in a kinase gain-of-function phenotype (71). Dopamine neurons from iPSC lines generated from a patient carrying this mutation were analyzed (55). The group reported that the cells had an increased accumulation of SNCA protein. Additionally, there was an increase in the expression of ROS-associated genes, including HSPB1, and increased susceptibility to ROS-associated cell death after exposure to hydrogen peroxide. Another set of parallel studies by another group using iPSC lines with the above mutation also observed a similar SNCA protein accumulation (72). Additionally, they reported neuronal morphology phenotypes including reduced neurite length. Finally, Orenstein et al. (56) looked at the role of and identified LRRK2 as a target of chaperone-mediated autophagy (CMA). When they looked at G2019S-containing dopaminergic neurons, LRRK2 degradation was compromised and that this resulted in the blockage of the CMA degradation pathway. They also observed phenotypes described earlier including neurite shortening and accumulation of SNCA which colocalized with lysosome-associated membrane protein 2A (LAMP2A) at the lysosomal membranes. Cooper et al. (58) assessed mitochondrial dysfunction associated with LRRK2 mutations (G2019S and R1441C). Patient iPSC-derived neurons exhibited a reduced basal oxygen consumption rate compared to healthy controls. Upon exposure of these neurons to high concentrations of hydrogen peroxide, the cells produced less glutathione (GSH) compared to controls, suggesting that the LRRK2 mutant dopaminergic neurons have impaired ability to respond to ROS stress. Additionally, the lines also contained shorter mitochondria. In vitro gene therapy has also been demonstrated successfully (57). The authors used ZFN technology to have successfully corrected the G2019S point mutation in two patient-derived iPSC lines. The gene-corrected lines had a restored neurite length to levels similar to the controls. Additionally, the G2019S genetically corrected lines did not demonstrate an SNCA accumulation as observed in mutant lines.
Exenatide promotes the autophagic function in the diabetic hippocampus: a review
Published in Egyptian Journal of Basic and Applied Sciences, 2022
Eman Mohammed Elsaeed, Ahmed Gamal Abdelghafour Hamad, Omnia S. Erfan, Mona A. El-Shahat, Fathy Abd Elghany Ebrahim
Autophagy has three different types: chaperone-mediated autophagy which deals with the unfolded soluble proteins, microautophagy which deals with the cytosolic components by invagination, and macroautophagy which deals with the cytoplasmic cargo by the ordered process of autophagy [18].