ELAVL4, splicing, and glutamatergic dysfunction precede neuron loss in MAPT mutation cerebral organoids

Human Induced Pluripotent Stem Cell Models of Frontotemporal Dementia With Tau Pathology

“…Patient and genecorrected iPSC-derived organoids were followed over 6 months of differentiation demonstrating accelerated differentiation of cortical glutamatergic neurons with earlier expression of glutamatergic signalling pathways and synaptic genes at 2 months and a significant reduction of excitatory deep and upper layer cortical neurons but not of interneurons at 4 and 6 months of culture of V337M organoids. These findings demonstrated selective excitatory neuron vulnerability in these organoids (Bowles et al, 2021). V337M organoids also showed a progressive upregulation and accumulation of total tau and p-tau, they demonstrated dysfunction of the early autophagy-lysosomal pathway, and they exhibited increased formation of stress granules.…”

“…These approaches may involve the exposure to oxidative stress, introduction of DNA damage or impairment of DNA repair in differentiating cells ( Miller et al, 2013 ), in part also addressing the limitation of lack of environmental cues. The culture of iPSC-derived cells as organoids ( Seo et al, 2017 ; Bowles et al, 2021 ) and the transplantation of patient neural cells into rodent brains ( Hargus et al, 2010 ) may provide additional alternatives since patient neurons could grow and communicate in a more physiological, three-dimensional context. The application of common immunohistochemical and biochemical tools as well as novel single cell technologies such as single cell proteomics or single cell RNA sequencing, as shown for MAPT V337M organoids ( Bowles et al, 2021 ), may be very helpful in this context to detect previously unrecognized disease-associated changes.…”

“…In a recent study, an isogenic organoid model of MAPT V337M-associated FTLD-tau was established to study disease-associated changes and mechanisms of early neural degeneration in a three-dimensional context using single cell RNA sequencing among other techniques ( Bowles et al, 2021 ). Patient and gene-corrected iPSC-derived organoids were followed over 6 months of differentiation demonstrating accelerated differentiation of cortical glutamatergic neurons with earlier expression of glutamatergic signalling pathways and synaptic genes at 2 months and a significant reduction of excitatory deep and upper layer cortical neurons but not of interneurons at 4 and 6 months of culture of V337M organoids.…”

“…V337M organoids also demonstrated an increased susceptibility to glutamate-induced excitotoxicity, which could be rescued by the application of glutamate receptor inhibitors and by the PIKFYVE kinase inhibitor apilimod, providing a potential therapeutic target. Interestingly, neuronal disease phenotypes in V337M organoids were paralleled by an astrocyte-mediated neuroinflammatory response with an upregulation of interleukin-6, interleukin-8 and neuroinflammation signaling pathways in V337M astrocytes ( Bowles et al, 2021 ). These findings highlight that iPSC-derived organoids represent an elegant platform to study neuronal but also glial pathology and, potentially, any glia-mediated mechanisms of neuronal degeneration over prolonged periods of time.…”

Rare Does Not Mean Worthless: How Rare Diseases Have Shaped Neurodevelopment Research in the NGS Era

“…Independently from the chosen protocol, organoids have so far been extremely useful for investigating early brain development in vitro better, and by implication, the study and understanding of disorders that are related to the early stages of neurodevelopment. As for classical models, organoids have been used extensively to study neurodevelopmental and neuropsychiatric disorders, including microcephaly [ 94 , 102 ], macrocephaly [ 103 ], lissencephaly [ 103 , 104 , 105 ], periventricular heterotopia [ 106 , 107 , 108 ], ASD [ 109 ], schizophrenia [ 110 ], Rett syndrome [ 111 ], fragile X syndrome [ 112 ], frontotemporal dementia [ 113 ], Schinzel–Giedion syndrome [ 65 ], and many others.…”