Abstract
Fragile X-associated tremor/ataxia syndrome (FXTAS) is a leading monogenic neurodegenerative disorder affecting premutation carriers of the fragile X (FMR1) gene. To investigate the underlying cellular neuropathology, we produced induced pluripotent stem cell-derived neurons from isogenic subclones of primary fibroblasts of a female premutation carrier, with each subclone bearing exclusively either the normal or the expanded (premutation) form of the FMR1 gene as the active allele. We show that neurons harboring the stably-active, expanded allele (EX-Xa) have reduced postsynaptic density protein 95 protein expression, reduced synaptic puncta density and reduced neurite length. Importantly, such neurons are also functionally abnormal, with calcium transients of higher amplitude and increased frequency than for neurons harboring the normal-active allele. Moreover, a sustained calcium elevation was found in the EX-Xa neurons after glutamate application. By excluding the individual genetic background variation, we have demonstrated neuronal phenotypes directly linked to the FMR1 premutation. Our approach represents a unique isogenic, X-chromosomal epigenetic model to aid the development of targeted therapeutics for FXTAS, and more broadly as a model for the study of common neurodevelopmental (e.g. autism) and neurodegenerative (e.g. Parkinsonism, dementias) disorders.
| Original language | English (US) |
|---|---|
| Article number | dds207 |
| Pages (from-to) | 3795-3805 |
| Number of pages | 11 |
| Journal | Human Molecular Genetics |
| Volume | 21 |
| Issue number | 17 |
| DOIs | |
| State | Published - Sep 2012 |
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ASJC Scopus subject areas
- Genetics
- Genetics(clinical)
- Molecular Biology
Cite this
Signaling defects in iPSC-derived fragile X premutation neurons. / Liu, Jing; Kościelska, Katarzyna A.; Cao, Zhengyu; Hulsizer, Susan; Grace, Natalie; Mitchell, Gaela; Nacey, Catherine; Githinji, Jackline; McGee, Jeannine; Garcia-Arocena, Dolores; Hagerman, Randi J; Nolta, Jan; Pessah, Isaac N; Hagerman, Paul J.
In: Human Molecular Genetics, Vol. 21, No. 17, dds207, 09.2012, p. 3795-3805.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Signaling defects in iPSC-derived fragile X premutation neurons
AU - Liu, Jing
AU - Kościelska, Katarzyna A.
AU - Cao, Zhengyu
AU - Hulsizer, Susan
AU - Grace, Natalie
AU - Mitchell, Gaela
AU - Nacey, Catherine
AU - Githinji, Jackline
AU - McGee, Jeannine
AU - Garcia-Arocena, Dolores
AU - Hagerman, Randi J
AU - Nolta, Jan
AU - Pessah, Isaac N
AU - Hagerman, Paul J
PY - 2012/9
Y1 - 2012/9
N2 - Fragile X-associated tremor/ataxia syndrome (FXTAS) is a leading monogenic neurodegenerative disorder affecting premutation carriers of the fragile X (FMR1) gene. To investigate the underlying cellular neuropathology, we produced induced pluripotent stem cell-derived neurons from isogenic subclones of primary fibroblasts of a female premutation carrier, with each subclone bearing exclusively either the normal or the expanded (premutation) form of the FMR1 gene as the active allele. We show that neurons harboring the stably-active, expanded allele (EX-Xa) have reduced postsynaptic density protein 95 protein expression, reduced synaptic puncta density and reduced neurite length. Importantly, such neurons are also functionally abnormal, with calcium transients of higher amplitude and increased frequency than for neurons harboring the normal-active allele. Moreover, a sustained calcium elevation was found in the EX-Xa neurons after glutamate application. By excluding the individual genetic background variation, we have demonstrated neuronal phenotypes directly linked to the FMR1 premutation. Our approach represents a unique isogenic, X-chromosomal epigenetic model to aid the development of targeted therapeutics for FXTAS, and more broadly as a model for the study of common neurodevelopmental (e.g. autism) and neurodegenerative (e.g. Parkinsonism, dementias) disorders.
AB - Fragile X-associated tremor/ataxia syndrome (FXTAS) is a leading monogenic neurodegenerative disorder affecting premutation carriers of the fragile X (FMR1) gene. To investigate the underlying cellular neuropathology, we produced induced pluripotent stem cell-derived neurons from isogenic subclones of primary fibroblasts of a female premutation carrier, with each subclone bearing exclusively either the normal or the expanded (premutation) form of the FMR1 gene as the active allele. We show that neurons harboring the stably-active, expanded allele (EX-Xa) have reduced postsynaptic density protein 95 protein expression, reduced synaptic puncta density and reduced neurite length. Importantly, such neurons are also functionally abnormal, with calcium transients of higher amplitude and increased frequency than for neurons harboring the normal-active allele. Moreover, a sustained calcium elevation was found in the EX-Xa neurons after glutamate application. By excluding the individual genetic background variation, we have demonstrated neuronal phenotypes directly linked to the FMR1 premutation. Our approach represents a unique isogenic, X-chromosomal epigenetic model to aid the development of targeted therapeutics for FXTAS, and more broadly as a model for the study of common neurodevelopmental (e.g. autism) and neurodegenerative (e.g. Parkinsonism, dementias) disorders.
UR - http://www.scopus.com/inward/record.url?scp=84865064735&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84865064735&partnerID=8YFLogxK
U2 - 10.1093/hmg/dds207
DO - 10.1093/hmg/dds207
M3 - Article
C2 - 22641815
AN - SCOPUS:84865064735
VL - 21
SP - 3795
EP - 3805
JO - Human Molecular Genetics
JF - Human Molecular Genetics
SN - 0964-6906
IS - 17
M1 - dds207
ER -