Multiplication of the<i>SNCA</i>locus exacerbates neuronal nuclear aging

Tagliafierro, Lidia; Zamora, Madison E.; Chiba‐Falek, Ornit

doi:10.1093/hmg/ddy355

Cited by 26 publications

(45 citation statements)

References 61 publications

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“…Potentially related to this, α‐synuclein accumulation and aggregation is not so far a common feature in iPSC‐derived models unless they are maintained in culture for extremely long periods of time. Therefore, more studies must be performed where aging of iPSC‐DA neurons is provoked pharmacologically or another method (Vera et al ; Tagliafierro et al ). Alternatively, technological advances in cell differentiation may improve our ability to directly convert patient somatic cells into specific neuronal populations (iNeurons) without altering the epigenetic profile.…”

Section: Patient‐derived Cell Lines Modeling Disease In a Dishmentioning

confidence: 99%

Cellular models of alpha‐synuclein toxicity and aggregation

Delenclos

Burgess

Lamprokostopoulou

et al. 2019

Journal of Neurochemistry

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Misfolding and aggregation of alpha‐synuclein (α‐synuclein) with concomitant cytotoxicity is a hallmark of Lewy body related disorders such as Parkinson’s disease, dementia with Lewy bodies, and multiple system atrophy. Although it plays a pivotal role in pathogenesis and disease progression, the function of α‐synuclein and the molecular mechanisms underlying α‐synuclein‐induced neurotoxicity in these diseases are still elusive. Many in vitro and in vivo experimental models mimicking α‐synuclein pathology such as oligomerization, toxicity and more recently neuronal propagation have been generated over the years. In particular, cellular models have been crucial for our comprehension of the pathogenic process of the disease and are beneficial for screening of molecules capable of modulating α‐synuclein toxicity. Here, we review α‐synuclein based cell culture models that reproduce some features of the neuronal populations affected in patients, from basic unicellular organisms to mammalian cell lines and primary neurons, to the cutting edge models of patient‐specific cell lines. These reprogrammed cells known as induced pluripotent stem cells (iPSCs) have garnered attention because they closely reproduce the characteristics of neurons found in patients and provide a valuable tool for mechanistic studies. We also discuss how different cell models may constitute powerful tools for high‐throughput screening of molecules capable of modulating α‐synuclein toxicity and prevention of its propagation. This article is part of the Special Issue “Synuclein”.

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Section: Patient‐derived Cell Lines Modeling Disease In a Dishmentioning

confidence: 99%

Cellular models of alpha‐synuclein toxicity and aggregation

Delenclos

Burgess

Lamprokostopoulou

et al. 2019

Journal of Neurochemistry

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“…The accumulation of insoluble α-Syn, expected to be part of the aggregation cascade of α-Syn, was detected in a diverse set of genetic PD models such as SNCA duplication (Prots et al, 2018), SNCA triplication (Mazzulli et al, 2016;Ludtmann et al, 2018;Tagliafierro et al, 2019) and the point mutations SNCA A53T (Ryan et al, 2013;Kouroupi et al, 2017) PARK2 V324A (Chung et al, 2016), PINK1 Q456X (Chung et al, 2016) and GBA N370S (Kim et al, 2018). This reproduces aggregation as the shared disease process of PD and underlines iPSC-derived models as an adequate tool to investigate synucleinopathies on a cellular level.…”

Section: Aggregationmentioning

confidence: 63%

“…Recently, premature aging was introduced to iPSC models of SNCA triplication by extended passaging at the NPC state. These aged neurons showed a higher α-Syn aggregation rate compared to the young SNCA triplication neurons (Tagliafierro et al, 2019). The incorporation of aging adds an additional layer of complexity that can be modeled by iPSC-derived PD neurons.…”

Section: Aggregationmentioning

confidence: 98%

“…Studies have so far added a variety of aging factors together with different PD-causing mutations, all of which resulted in a higher susceptibility. Several strategies have been applied to induce premature aging, e.g., telomerase inhibition (Vera et al, 2016), progerin expression (Miller et al, 2013) and higher NPC passaging (Tagliafierro et al, 2019). The susceptibility towards the aging factors was not specific to a certain mutation, as shown for PARK2 V324A (Miller et al, 2013) PINK1 Q456X (Miller et al, 2013;Vera et al, 2016) and SNCA triplication cases (Miller et al, 2013;Vera et al, 2016;Oh, 2019).…”

Section: Stressor Responsementioning

confidence: 99%

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Modeling Cell-Cell Interactions in Parkinson’s Disease Using Human Stem Cell-Based Models

Simmnacher

Lanfer

Rizo

et al. 2020

Front. Cell. Neurosci.

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Parkinson's disease (PD) is the most frequently occurring movement disorder, with an increasing incidence due to an aging population. For many years, the post-mortem brain was regarded as the gold standard for the analysis of the human pathology of this disease. However, modern stem cell technologies, including the analysis of patient-specific neurons and glial cells, have opened up new avenues for dissecting the pathologic mechanisms of PD. Most data on morphological changes, such as cell death or changes in neurite complexity, or functional deficits were acquired in 2D and few in 3D models. This review will examine the prerequisites for human disease modeling in PD, covering the generation of midbrain neurons, 3D organoid midbrain models, the selection of controls including genetically engineered lines, and the study of cell-cell interactions. We will present major disease phenotypes in human in vitro models of PD, focusing on those phenotypes that have been detected in genetic and sporadic PD models. An additional point covered in this review will be the use of induced pluripotent stem cell (iPSC)-derived technologies to model cell-cell interactions in PD.

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“…Another recent study showed that misfolded α-synuclein breaks the genomic DNA strand by opening a DNA nick. This DNA damage can be synergistic with Fe ions, promoting the death of SNCA triplication iPSC-derived neural progenitor cells [31]. In addition, α-synuclein may induce neurotoxicity by accelerating the cell cycle [32].…”

Section: Nuclear Toxicitymentioning

confidence: 99%

Modeling Parkinson’s Disease Using Induced Pluripotent Stem Cells

Mao

Fan

et al. 2020

Stem Cells International

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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.

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Multiplication of theSNCAlocus exacerbates neuronal nuclear aging

Cited by 26 publications

References 61 publications

Cellular models of alpha‐synuclein toxicity and aggregation

Cellular models of alpha‐synuclein toxicity and aggregation

Modeling Cell-Cell Interactions in Parkinson’s Disease Using Human Stem Cell-Based Models

Modeling Parkinson’s Disease Using Induced Pluripotent Stem Cells

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