Modelling Parkinson’s Disease: iPSCs towards Better Understanding of Human Pathology

Avazzadeh, Sahar; Baena, Jara Maria; Keighron, Cameron; Feller-Sanchez, Yajaira; Quinlan, Leo R.

doi:10.3390/brainsci11030373

Cited by 26 publications

(21 citation statements)

References 197 publications

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“…However, this increase was not significant compared to DA neuronal culture from a healthy donor. The absence of LB-like α-syn accumulation is a general limitation of currently available cellular models of PD [12]. Importantly, we observed punctated accumulation of pathological α-syn (pS129 positive) next to the nucleus of cells derived from fPD lines, spatially and morphologically resembling LBs.…”

Section: Discussionmentioning

confidence: 63%

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Induced Pluripotent Stem Cell-Derived Dopaminergic Neurons from Familial Parkinson’s Disease Patients Display α-Synuclein Pathology and Abnormal Mitochondrial Morphology

Diao

Wang

Becerra-Calixto

et al. 2021

Cells

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Accumulation of α-synuclein (α-syn) into Lewy bodies (LBs) and mitochondrial abnormalities are the two cardinal pathobiological features of Parkinson’s disease (PD), which are associated with the loss of dopaminergic neurons. Although α-syn accumulates in many different cellular and mouse models, these models generally lack LB features. Here, we generated midbrain dopaminergic (mDA) neuronal cultures from induced pluripotent stem cells (iPSCs) derived from familial PD (fPD) patients and healthy controls. We show that mDA neuronal cultures from fPD patients with A53T mutation and α-syn gene (SNCA) triplication display pathological α-syn deposits, which spatially and morphologically resemble LBs. Importantly, we did not find any apparent accumulation of pathological α-syn in mDA neuronal culture derived from a healthy donor. Furthermore, we show that there are morphological abnormalities in the mitochondrial network in mDA neuronal cultures from fPD patients. Consequently, these cells were more susceptible to mitochondrial damage compared with healthy donor-derived mDA neuronal cultures. Our results indicate that the iPSC-derived mDA neuronal culture platform can be used to investigate the spatiotemporal appearance of LBs, as well as their composition, architecture, and relationship with mitochondrial abnormalities.

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Section: Discussionmentioning

confidence: 63%

“…DA neuronal cultures derived from fPD patients manifested different aspects of PD pathology (reviewed by Sahar Avazzadeh et al, 2021 (ref. [12])). Although α-syn accumulation in fPD-iPSC-derived DA neurons has been reported in multiple studies, the formation of LB-like structures in these cells has not been shown.…”

Section: Introductionmentioning

confidence: 99%

Induced Pluripotent Stem Cell-Derived Dopaminergic Neurons from Familial Parkinson’s Disease Patients Display α-Synuclein Pathology and Abnormal Mitochondrial Morphology

Diao

Wang

Becerra-Calixto

et al. 2021

Cells

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“…α-synuclein is encoded by the SNCA gene which is found on chromosome 4 (4q21. [3][4][5][6][7][8][9][10][11][12][13][14][15][16][17][18][19][20][21][22] and mutations of this gene show an autosomal dominant pattern of inheritance.…”

Section: Introductionmentioning

confidence: 99%

“…This type of approach is commonly known as 'disease in a dish' modelling (12) (Figure 1). This methodology has the advantage of maintaining the patient's complete genetic background and allows the impact of certain key mutations on pathophysiology to be studied, allowing the characterization of key cellular mutation-based phenotypes in complex diseases such as Parkinson's disease (13). Dopaminergic (DA) neurons are the main cell type used to study neurodegeneration in Parkinson's disease using several different protocols.…”

Section: Introductionmentioning

confidence: 99%

“…This type of approach is commonly known as ‘ disease in a dish ’ modeling [ 12 ] ( Figure 1 ). This methodology has the advantage of maintaining the patient’s complete genetic background and allows the impact of certain key mutations on pathophysiology to be studied, allowing the characterization of key cellular mutation-based phenotypes in complex diseases such as PD [ 13 ].…”

Section: Introductionmentioning

confidence: 99%

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α-synuclein pathogenesis in hiPSC models of Parkinson’s disease

2021

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α-synuclein is an increasingly prominent player in the pathology of a variety of neurodegenerative conditions. Parkinson’s disease (PD) is a neurodegenerative disorder that affects mainly the dopaminergic neurons in the substantia nigra of the brain. Typical of PD pathology is the finding of protein aggregations termed ‘Lewy bodies’ in the brain regions affected. α-synuclein is implicated in many disease states including dementia with Lewy bodies and Alzheimer’s disease. However, PD is the most common synucleinopathy and continues to be a significant focus of PD research in terms of the α-synuclein Lewy body pathology. Mutations in several genes are associated with PD development including SNCA, which encodes α-synuclein. A variety of model systems have been employed to study α-synuclein physiology and pathophysiology in an attempt to relate more closely to PD pathology. These models include cellular and animal system exploring transgenic technologies, viral vector expression and knockdown approaches, and models to study the potential prion protein-like effects of α-synuclein. The current review focuses on human induced pluripotent stem cell (iPSC) models with a specific focus on mutations or multiplications of the SNCA gene. iPSCs are a rapidly evolving technology with huge promise in the study of normal physiology and disease modeling in vitro. The ability to maintain a patient's genetic background and replicate similar cell phenotypes make iPSCs a powerful tool in the study of neurological diseases. This review focus on the current knowledge about α-synuclein physiological function as well as its role in PD pathogenesis based on human iPSC models.

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Evaluation of type 1 diabetes mellitus as a risk factor of Parkinson's disease in a Drosophila model

et al. 2023

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Diabetes mellitus (DM) is a chronic metabolic disease characterized by high blood glucose levels, resulting from insulin dysregulation. Parkinson's disease (PD) is the most common neurodegenerative motor disorder caused by the selective loss of dopaminergic (DA) neurons in the substantia nigra pars compacta. DM and PD are both age‐associated diseases that are turning into epidemics worldwide. Previous studies have indicated that type 2 DM might be a risk factor of developing PD. However, scarce information about the link between type 1 DM (T1DM) and PD does exist. In this work, we have generated a Drosophila model of T1DM based on insulin deficiency to evaluate if T1DM could be a risk factor to trigger PD onset. As expected, model flies exhibited T1DM‐related phenotypes such as insulin deficiency, increased content of carbohydrates and glycogen, and reduced activity of insulin signaling. Interestingly, our results also demonstrated that T1DM model flies presented locomotor defects as well as reduced levels of tyrosine hydroxylase (a marker of DA neurons) in brains, which are typical PD‐related phenotypes. In addition, T1DM model flies showed elevated oxidative stress levels, which could be causative of DA neurodegeneration. Therefore, our results indicate that T1DM might be a risk factor of developing PD, and encourage further studies to shed light into the exact link between both diseases.

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Modelling Parkinson’s Disease: iPSCs towards Better Understanding of Human Pathology

Cited by 26 publications

References 197 publications

Induced Pluripotent Stem Cell-Derived Dopaminergic Neurons from Familial Parkinson’s Disease Patients Display α-Synuclein Pathology and Abnormal Mitochondrial Morphology

Induced Pluripotent Stem Cell-Derived Dopaminergic Neurons from Familial Parkinson’s Disease Patients Display α-Synuclein Pathology and Abnormal Mitochondrial Morphology

α-synuclein pathogenesis in hiPSC models of Parkinson’s disease

Evaluation of type 1 diabetes mellitus as a risk factor of Parkinson's disease in a Drosophila model

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