Searching across hundreds of databases

Our searching services are busy right now. Your search will reload in five seconds.

Forgot Password

If you have forgotten your password you can enter your email here and get a temporary password sent to your email.

Forgot Password

If you have forgotten your password you can enter your email here and get a temporary password sent to your email.

Signaling defects in iPSC-derived fragile X premutation neurons.

Human molecular genetics | Sep 1, 2012

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.

Pubmed ID: 22641815 RIS Download

Mesh terms: Action Potentials | Alleles | Calcium | Cell Differentiation | Clone Cells | Female | Fibroblasts | Fragile X Mental Retardation Protein | Fragile X Syndrome | Gene Expression Regulation | Humans | Induced Pluripotent Stem Cells | Middle Aged | Mutation | Neurons | RNA, Messenger | Signal Transduction | Synapses | Tissue Donors | X Chromosome Inactivation

Research tools detected in this publication

None found

Data used in this publication

Associated grants

  • Agency: NIGMS NIH HHS, Id: R01 GM099688
  • Agency: NIEHS NIH HHS, Id: P01 ES011269
  • Agency: NIA NIH HHS, Id: RL1 AG032115
  • Agency: NIA NIH HHS, Id: RL1 AG032119
  • Agency: NIA NIH HHS, Id: RC1 AG036022
  • Agency: NIDCR NIH HHS, Id: UL1 DE019583

Publication data is provided by the National Library of Medicine ® and PubMed ®. Data is retrieved from PubMed ® on a weekly schedule. For terms and conditions see the National Library of Medicine Terms and Conditions.