347 Alpha-Synuclein Induces the Unfolded Protein Response in Parkinson's Disease Patient-Specific SNCA Triplication iPSC-Derived Neurons

Parkinson’s disease (PD) is a multifactorial age-related movement disorder in which defects of both mitochondria and the endoplasmic reticulum (ER) have been reported. The unfolded protein response (UPR) has emerged as a key cellular dysfunction associated with the etiology of the disease. The UPR involves a coordinated response initiated in the endoplasmic reticulum that grants the correct folding of proteins. This review gives insights on the ER and its functioning; the UPR signaling cascades; and the link between ER stress, UPR activation, and physiopathology of PD. Thus, post-mortem studies and data obtained by either in vitro and in vivo pharmacological approaches or by genetic modulation of PD causative genes are described. Further, we discuss the relevance and impact of the UPR to sporadic and genetic PD pathology.

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Activation of the Unfolded Protein Response in Parkinson's disease

Frontiers in Cellular Neuroscience ◽

10.3389/conf.fncel.2019.01.00051 ◽

2019 ◽

Vol 13 ◽

Author(s):

Andreia Carvalho ◽

Catarina Ranito ◽

Carolina Tavares ◽

Margarida Castro-Caldas ◽

Elsa Rodrigues ◽

...

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Unfolded Protein Response ◽

Unfolded Protein ◽

The Unfolded Protein Response ◽

Protein Response

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Endoplasmic Reticulum Stress and the Unfolded Protein Response in Cellular Models of Parkinson's Disease

Journal of Neuroscience ◽

10.1523/jneurosci.22-24-10690.2002 ◽

2002 ◽

Vol 22 (24) ◽

pp. 10690-10698 ◽

Cited By ~ 384

Author(s):

Elizabeth J. Ryu ◽

Heather P. Harding ◽

James M. Angelastro ◽

Ottavio V. Vitolo ◽

David Ron ◽

...

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Endoplasmic Reticulum ◽

Endoplasmic Reticulum Stress ◽

Unfolded Protein Response ◽

Unfolded Protein ◽

Cellular Models ◽

The Unfolded Protein Response ◽

Protein Response

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Enforced dimerization between XBP1s and ATF6f enhances the protective effects of the unfolded protein response (UPR) in models of neurodegeneration

10.1101/2020.11.17.387480 ◽

2020 ◽

Author(s):

René L. Vidal ◽

Denisse Sepulveda ◽

Paulina Troncoso-Escudero ◽

Paula Garcia-Huerta ◽

Constanza Gonzalez ◽

...

Keyword(s):

Gene Expression ◽

Unfolded Protein Response ◽

Target Genes ◽

Cell Function ◽

Alpha Synuclein ◽

Protective Effects ◽

Unfolded Protein ◽

The Unfolded Protein Response ◽

Protein Response

AbstractAlteration to endoplasmic reticulum (ER) proteostasis is observed on a variety of neurodegenerative diseases associated with abnormal protein aggregation. Activation of the unfolded protein response (UPR) enables an adaptive reaction to recover ER proteostasis and cell function. The UPR is initiated by specialized stress sensors that engage gene expression programs through the concerted action of the transcription factors ATF4, ATF6f, and XBP1s. Although UPR signaling is generally studied as unique linear signaling branches, correlative evidence suggests that ATF6f and XBP1s may physically interact to regulate a subset of UPR-target genes. Here, we designed an ATF6f-XBP1s fusion protein termed UPRplus that behaves as a heterodimer in terms of its selective transcriptional activity. Cell-based studies demonstrated that UPRplus has stronger an effect in reducing the abnormal aggregation of mutant huntingtin and alpha-synuclein when compared to XBP1s or ATF6 alone. We developed a gene transfer approach to deliver UPRplus into the brain using adeno-associated viruses (AAVs) and demonstrated potent neuroprotection in vivo in preclinical models of Parkinson’s and Huntington’s disease. These results support the concept where directing UPR-mediated gene expression toward specific adaptive programs may serve as a possible strategy to optimize the beneficial effects of the pathway in different disease conditions.

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In vivo phenotyping of Parkinson-specific stem cells reveals increased a-Synuclein levels but no spreading

10.1101/140178 ◽

2017 ◽

Cited By ~ 1

Author(s):

Kathrin Hemmer ◽

Lisa M. Smits ◽

Silvia Bolognin ◽

Jens C. Schwamborn

Keyword(s):

Parkinson’S Disease ◽

Stem Cells ◽

Parkinson's Disease ◽

Mouse Brain ◽

Disease Modeling ◽

Disease Patient ◽

Alpha Synuclein ◽

Patient Specific ◽

Species Barrier

AbstractParkinson′s disease is a progressive age-associated neurological disorder. One of the major neuropathological hallmarks of Parkinson’s disease is the appearance of protein aggregates, mainly consisting of the protein alpha-Synuclein. These aggregates have been described both in genetic as well as idiopathic forms of the disease. Currently, Parkinson’s disease patient-specific induced pluripotent stem cells (iPSCs) are mainly used for in vitro disease modeling or for experimental cell replacement approaches. Here, we demonstrate that these cells can be used for in vivo disease modeling. We show that Parkinson’s disease patient-specific, iPSC-derived neurons carrying the LRRK2-G2019S mutation show an upregulation of alpha-Synuclein after transplantation in the mouse brain. However, further investigations indicate that the increased human alpha-Synuclein levels fail to induce spreading or aggregation in the mouse brain. We therefore conclude that grafting of these cells into the mouse brain is suitable for cell autonomous in vivo disease modeling but has strong limitations beyond that. Furthermore, our results support the hypothesis that there might be a species barrier between human to mouse concerning alpha-Synuclein spreading.

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