Genomic Analysis Reveals Disruption of Striatal Neuronal Development and Therapeutic Targets in Human Huntington’s Disease Neural Stem Cells

Ring, Karen; An, Mahru C.; Zhang, Ningzhe; O’Brien, Robert; Ramos, Eliana Marisa; Gao, Fuying; Atwood, Robert C.; Bailus, Barbara J.; Melov, Simon; Mooney, Sean D.; Coppola, Giovanni; Ellerby, Lisa M.

doi:10.1016/j.stemcr.2015.11.005

Cited by 97 publications

(154 citation statements)

References 53 publications

(70 reference statements)

Supporting

Mentioning

133

Contrasting

Unclassified

Order By: Relevance

“…These findings collectively indicate that undifferentiated cells harboring the LIN28A mutation are already poised to develop the disorder. These data are consistent with reports demonstrating disease phenotypes and perturbed expression of disease‐associated genes in iPSCs and NSCs derived from Huntington's disease patients (An et al , ; Camnasio et al , ; Ring et al , ). All of these findings suggest that the first steps in disease pathogenesis of adult‐onset neurodegenerative diseases may occur during embryonic development (Humbert, ; Brennand, ).…”

Section: Resultssupporting

confidence: 92%

LIN 28A loss of function is associated with Parkinson's disease pathogenesis

Chang

Choi

et al. 2019

The EMBO Journal

View full text Add to dashboard Cite

Parkinson's disease (PD) is neurodegenerative movement disorder characterized by degeneration of midbrain‐type dopamine (mDA) neurons in the substantia nigra (SN). The RNA‐binding protein Lin28 plays a role in neuronal stem cell development and neuronal differentiation. In this study, we reveal that Lin28 conditional knockout (cKO) mice show degeneration of mDA neurons in the SN, as well as PD‐related behavioral deficits. We identify a loss‐of‐function variant of LIN28A (R192G substitution) in two early‐onset PD patients. Using an isogenic human embryonic stem cell (hESC)/human induced pluripotent stem cell (hiPSC)‐based disease model, we find that the Lin28 R192G variant leads to developmental defects and PD‐related phenotypes in mDA neuronal cells that can be rescued by expression of wild‐type Lin28A. Cell transplantation experiments in PD model rats show that correction of the LIN28A variant in the donor patient (pt)‐hiPSCs leads to improved behavioral phenotypes. Our data link LIN28A to PD pathogenesis and suggest future personalized medicine targeting this variant in patients.

show abstract

Section: Resultssupporting

confidence: 92%

LIN 28A loss of function is associated with Parkinson's disease pathogenesis

Chang

Choi

et al. 2019

The EMBO Journal

View full text Add to dashboard Cite

show abstract

“…TGFβ signaling is implicated as a ‘switching factor’ whose levels and temporal activity require tight regulation during development to determine neuronal cell fate 22 . This signaling network was disrupted in neural stem cells from HD patient iPSCs 23 . Highlighted in this network were genes overlapping the IPA-predicted regulators and genes that are major hubs with direct connections to other genes in the larger network, suggesting an association with HD.…”

Section: Resultsmentioning

confidence: 99%

Developmental alterations in Huntington's disease neural cells and pharmacological rescue in cells and mice

Lim¹,

Salazar²,

Wilton³

et al. 2017

Nat Neurosci

187

172

View full text Add to dashboard Cite

Neural cultures derived from Huntington’s disease (HD) patient-derived induced pluripotent stem cells were used for ‘omics’ analyses to identify mechanisms underlying neurodegeneration. RNA-seq analysis identified genes in glutamate and GABA signaling, axonal guidance and calcium influx whose expression was decreased in HD cultures. One-third of gene changes were in pathways regulating neuronal development and maturation. When mapped to stages of mouse striatal development, the profiles aligned with earlier embryonic stages of neuronal differentiation. We observed a strong correlation between HD-related histone marks, gene expression and unique peak profiles associated with dysregulated genes, suggesting a coordinated epigenetic program. Treatment with isoxazole-9, which targets key dysregulated pathways, led to amelioration of expanded polyglutamine repeat-associated phenotypes in neural cells and of cognitive impairment and synaptic pathology in HD model R6/2 mice. These data suggest that mutant huntingtin impairs neurodevelopmental pathways that could disrupt synaptic homeostasis and increase vulnerability to the pathologic consequence of expanded polyglutamine repeats over time.

show abstract

“…demonstrated that TGF- β signaling pathway is altered in HD NSC with 72 CAGs that leads to higher expression of TGF- β . Furthermore, TGF- β 1 plays neuroprotective role in the NSC models and together with netrin-1 can reduce caspase 3/7 activity [94]. …”

Section: Ipscs Providing New Tools For Developing Treatments For Cmentioning

confidence: 99%

Generation of Cholinergic and Dopaminergic Interneurons from Human Pluripotent Stem Cells as a Relevant Tool for In Vitro Modeling of Neurological Disorders Pathology and Therapy

Ochałek

Szczesna

Petazzi

et al. 2016

Stem Cells International

View full text Add to dashboard Cite

The cellular and molecular bases of neurological diseases have been studied for decades; however, the underlying mechanisms are not yet fully elucidated. Compared with other disorders, diseases of the nervous system have been very difficult to study mainly due to the inaccessibility of the human brain and live neurons in vivo or in vitro and difficulties in examination of human postmortem brain tissue. Despite the availability of various genetically engineered animal models, these systems are still not adequate enough due to species variation and differences in genetic background. Human induced pluripotent stem cells (hiPSCs) reprogrammed from patient somatic cells possess the potential to differentiate into any cell type, including neural progenitor cells and postmitotic neurons; thus, they open a new area to in vitro modeling of neurological diseases and their potential treatment. Currently, many protocols for generation of various neuronal subtypes are being developed; however, most of them still require further optimization. Here, we highlight accomplishments made in the generation of dopaminergic and cholinergic neurons, the two subtypes most affected in Alzheimer's and Parkinson's diseases and indirectly affected in Huntington's disease. Furthermore, we discuss the potential role of hiPSC-derived neurons in the modeling and treatment of neurological diseases related to dopaminergic and cholinergic system dysfunction.

show abstract

Genomic Analysis Reveals Disruption of Striatal Neuronal Development and Therapeutic Targets in Human Huntington’s Disease Neural Stem Cells

Cited by 97 publications

References 53 publications

LIN 28A loss of function is associated with Parkinson's disease pathogenesis

LIN 28A loss of function is associated with Parkinson's disease pathogenesis

Developmental alterations in Huntington's disease neural cells and pharmacological rescue in cells and mice

Generation of Cholinergic and Dopaminergic Interneurons from Human Pluripotent Stem Cells as a Relevant Tool for In Vitro Modeling of Neurological Disorders Pathology and Therapy

Contact Info

Product

Resources

About