Impaired inhibitory GABAergic synaptic transmission and transcription studied in single neurons by Patch-seq in Huntington's disease.
Foteini ParaskevopoulouPoorya ParviziGökçe SengerNurcan TuncbagChristian RosenmundFerah YildirimPublished in: Proceedings of the National Academy of Sciences of the United States of America (2021)
Transcriptional dysregulation in Huntington's disease (HD) causes functional deficits in striatal neurons. Here, we performed Patch-sequencing (Patch-seq) in an in vitro HD model to investigate the effects of mutant Huntingtin (Htt) on synaptic transmission and gene transcription in single striatal neurons. We found that expression of mutant Htt decreased the synaptic output of striatal neurons in a cell autonomous fashion and identified a number of genes whose dysregulation was correlated with physiological deficiencies in mutant Htt neurons. In support of a pivotal role for epigenetic mechanisms in HD pathophysiology, we found that inhibiting histone deacetylase 1/3 activities rectified several functional and morphological deficits and alleviated the aberrant transcriptional profiles in mutant Htt neurons. With this study, we demonstrate that Patch-seq technology can be applied both to better understand molecular mechanisms underlying a complex neurological disease at the single-cell level and to provide a platform for screening for therapeutics for the disease.
Keyphrases
- single cell
- spinal cord
- rna seq
- genome wide
- gene expression
- transcription factor
- parkinson disease
- histone deacetylase
- traumatic brain injury
- dna methylation
- wild type
- poor prognosis
- stem cells
- signaling pathway
- copy number
- small molecule
- genome wide identification
- prefrontal cortex
- oxidative stress
- blood brain barrier
- cell therapy
- long non coding rna
- mesenchymal stem cells
- binding protein
- genome wide analysis
- solid state