Abstract
Parkinson's disease (PD) is the second most common neurodegenerative disease. The molecular mechanisms of PD at the cellular level involve oxidative stress, mitochondrial dysfunction, autophagy, axonal transport, and neuroinflammation. Induced pluripotent stem cells (iPSCs) with patient-specific genetic background are capable of directed differentiation into dopaminergic neurons. Cell models based on iPSCs are powerful tools for studying the molecular mechanisms of PD. The iPSCs used for PD studies were mainly from patients carrying mutations in synuclein alpha (SNCA), leucine-rich repeat kinase 2 (LRRK2), PTEN-induced putative kinase 1 (PINK1), parkin RBR E3 ubiquitin protein ligase (PARK2), cytoplasmic protein sorting 35 (VPS35), and variants in glucosidase beta acid (GBA). In this review, we summarized the advances in molecular mechanisms of Parkinson's disease using iPSC models.
Highlights
Parkinson’s disease (PD) is the second most common neurodegenerative disease, which is characterized by static tremors, rigidity, bradykinesia, and postural instability
synuclein alpha (SNCA), leucine-rich repeat kinase 2 (LRRK2), and VPS35 are associated with PD in autosomal dominant forms, and PTEN-Induced Kinase 1 (PINK1) and PARK2 are associated with PD in autosomal recessive forms
We summarized the current work on Induced pluripotent stem cells (iPSCs) models with mutations in SNCA, LRRK2, PINK1/Park2, VPS35, and glucosidase beta acid (GBA)
Summary
Parkinson’s disease (PD) is the second most common neurodegenerative disease, which is characterized by static tremors, rigidity, bradykinesia, and postural instability. A study showed that in SNCA triplication iPSCderived mDA neurons, accumulated α-synuclein disrupts RAB1a-mediated hydrolase transport and reduces lysosomal function through an abnormal association with the cisGolgi-binding factor GM130. Overexpression of RAB1a restores the Golgi structure, improves hydrolase transport and activity, and reduces pathological α-synuclein in patient neurons [43] Consistent with these findings, another study showed that in SNCA triplication iPSC-derived DA neurons, α-synuclein is reduced by a noninhibitory small molecule of β-glucocerebrosidase (GCase), which is sufficient to reverse the downstream cytopathies, including hydrolase maturation and perturbation of lysosomal dysfunction [44]. Mutations in LRRK2 G2019S can cause aberrations of mitochondrial morphology and function, an increase in mitochondrial number and mitochondrial debris, a decrease in mitochondrial membrane potential This mitochondrial defect was found in the LRRK2 G2019S iPSC-derived neuroepithelial stem cells in Walter’s study [67].
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