Synaptic decline precedes dopaminergic neuronal loss in human midbrain organoids harboring a triplication of the SNCA gene
Modamio, J.; Saraiva, C.; Gomez-Giro, G.; Nickels, S. L.; Jarazo, J.; Antony, P.; Barbuti, P.; Halder, R.; Jaeger, C.; Krueger, R.; Glaab, E.; Schwamborn, J. C.
Show abstract
1.Increased levels of the protein alpha-synuclein (-syn) are associated with the development of neurodegenerative diseases like Parkinsons disease (PD). In physiological conditions, -syn modulates synaptic plasticity, neurogenesis and neuronal survival. However, its pathogenic accumulation and aggregation results in toxicity and neurodegeneration. Here, we used a PD patient specific midbrain organoid model derived from induced pluripotent stem cells harboring a triplication in the SNCA gene to study PD-associated phenotypes. The model recapitulates the two main hallmarks of PD, which are -syn aggregation and loss of dopaminergic neurons. Additionally, impairments in astrocyte differentiation were detected. Transcriptomics data indicate that synaptic function is impaired in PD specific midbrain organoids. This is further confirmed by alterations in synapse number and electrophysiological activity. We found that synaptic decline precedes neurodegeneration. Finally, this study substantiates that patient specific midbrain organoids allow a personalized phenotyping, which make them an interesting tool for precision medicine and drug discovery.
Matching journals
The top 3 journals account for 50% of the predicted probability mass.
Similar papers in this journal
- Dopamine and cortical iPSC-derived neurons with different Parkinsonian mutations show variation in lysosomal and mitochondrial dysfunction: implications for protein deposition versus selective cell loss 96%
- SNCA triplication disrupts proteostasis and extracellular architecture prior to neurodegeneration in human midbrain organoids 95%
- Regulators of proteostasis are translationally repressed in fibroblasts from sporadic and LRRK2-G2019S Parkinson's patients 95%
Similar papers in this journal
- The LRRK2 kinase substrates Rab8a and Rab10 contribute complementary but distinct disease-relevant phenotypes in human neurons 96%
- Sonlicromanol improves neuronal network dysfunction and transcriptome changes linked to m.3243A > G heteroplasmy in iPSC-derived neurons 96%
- A human in vitro neuronal model for studying homeostatic plasticity at the network level 95%
Similar papers in this journal
- Bioenergetic and Protein Processing Imbalances Synergize in iPSC-Dopamine neurons from Individuals with Idiopathic Parkinsons Disease 97%
- Dopamine-iron homeostasis interaction rescues mitochondrial fitness in Parkinson's disease 96%
- Chchd10 Or Chchd2 Are Not Required For Human Motor Neuron Differentiation In Vitro But Modify Synaptic Transcriptomes 95%
Similar papers in this journal
Similar papers in this journal
- Dopamine transporter and synaptic vesicle sorting defects initiate auxilin-linked Parkinson's disease 96%
- Increased burden of rare risk variants across gene expression networks predisposes to sporadic Parkinson's disease 96%
- An integrated genomic approach to dissect the genetic landscape regulating the cell-to-cell transfer of a-synuclein 96%
"Similar papers" are the closest papers from that journal in the model's embedding space. They show what the match is built on, but the ranking comes mostly from a classifier over the whole training set, not from these examples alone.