Abstract
Parkinson’s disease (PD) and atypical parkinsonian syndromes are age-dependent multifactorial neurodegenerative diseases, which are clinically characterized by bradykinesia, tremor, muscle rigidity and postural instability. Although these diseases share several common clinical phenotypes, their pathophysiological aspects vary among the disease categories. Extensive animal-based approaches, as well as postmortem studies, have provided important insights into the disease mechanisms and potential therapeutic targets. However, the exact pathological mechanisms triggering such diseases still remain elusive. Furthermore, the effects of drugs observed in animal models are not always reproduced in human clinical trials. By using induced pluripotent stem cell (iPSC) technology, it has become possible to establish patient-specific iPSCs from their somatic cells and to effectively differentiate these iPSCs into different types of neurons, reproducing some key aspects of the disease phenotypes in vitro. In this review, we summarize recent findings from iPSC-based modeling of PD and several atypical parkinsonian syndromes including multiple system atrophy, frontotemporal dementia and parkinsonism linked to chromosome 17 and Perry syndrome. Furthermore, we discuss future challenges and prospects for modeling and understanding PD and atypical parkinsonian syndromes.
Highlights
Parkinson’s disease (PD) and multiple system atrophy (MSA) are pathologically linked to α-synucleinopathy, with the exceptions of parkin RBR E3 ubiquitin protein ligase (PRKN) and Leucine-Rich Repeat Kinase 2 (LRRK2) [13]; progressive supranuclear palsy (PSP), corticobasal degeneration (CBD) and FTDP-17 associated with microtubule-associated protein tau (MAPT) gene mutations (FTDP-17 (MAPT)) are linked to tauopathy; Perry syndrome and FTDP-17 associated with progranulin (GRN) gene mutations (FTDP-17 (GRN)) are linked to TAR DNA-binding protein of 43 kDa (TDP-43) proteinopathy
This study revealed that oligodendrocytes were able to produce α-synuclein inside of their own cells during their maturation in vitro; the origin of aggregated α-synuclein found in oligodendrocytes of MSA patients still remains unclear
Increased attention has been paid to progerin with the aim of advancing induced pluripotent stem cell (iPSC) research that handles premature aging disorders including Hutchinson-Gilford progeria syndrome (HGPS) [93]; progression in this field of research may contribute to identifying factors accelerating research on clinical phenotypes in neurodegenerative diseases
Summary
Parkinson’s disease (PD) and atypical parkinsonian syndromes are age-related, progressive neurodegenerative diseases that are clinically characterized by parkinsonism including bradykinesia, tremor, muscle rigidity and postural instability. Atypical parkinsonian syndromes exhibit parkinsonism due to loss of DA neurons caused by different pathological mechanisms. These diseases may accompany dementia associated with degeneration of cortical neurons. Atypical parkinsonian syndromes commonly include multiple system atrophy (MSA), progressive supranuclear palsy (PSP) and corticobasal degeneration (CBD). PD and MSA are pathologically linked to α-synucleinopathy, with the exceptions of parkin RBR E3 ubiquitin protein ligase (PRKN) and LRRK2 [13]; PSP, CBD and FTDP-17 associated with MAPT gene mutations (FTDP-17 (MAPT)) are linked to tauopathy; Perry syndrome and FTDP-17 associated with progranulin (GRN) gene mutations (FTDP-17 (GRN)) are linked to TAR DNA-binding protein of 43 kDa (TDP-43) proteinopathy. This article focuses on iPSC-based models of PD and some representative atypical parkinsonian syndromes
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