TY - JOUR
T1 - Single-Cell RNA-seq Reveals Profound Alterations in Mechanosensitive Dorsal Root Ganglion Neurons with Vitamin E Deficiency
AU - Finno, Carrie J.
AU - Peterson, Janel
AU - Kang, Mincheol
AU - Park, Seojin
AU - Bordbari, Matthew H.
AU - Durbin-Johnson, Blythe
AU - Settles, Matthew
AU - Perez-Flores, Maria C.
AU - Lee, Jeong H.
AU - Yamoah, Ebenezer N.
PY - 2019/11/22
Y1 - 2019/11/22
N2 - Ninety percent of Americans consume less than the estimated average requirements of dietary vitamin E (vitE). Severe vitE deficiency due to genetic mutations in the tocopherol transfer protein (TTPA) in humans results in ataxia with vitE deficiency (AVED), with proprioceptive deficits and somatosensory degeneration arising from dorsal root ganglia neurons (DRGNs). Single-cell RNA-sequencing of DRGNs was performed in Ttpa−/− mice, an established model of AVED. In stark contrast to expected changes in proprioceptive neurons, Ttpa−/− DRGNs showed marked upregulation of voltage-gated Ca2+ and K+ channels in mechanosensitive, tyrosine-hydroxylase positive (TH+) DRGNs. The ensuing significant conductance changes resulted in reduced excitability in mechanosensitive Ttpa−/− DRGNs. A highly supplemented vitE diet (600 mg dl-α-tocopheryl acetate/kg diet) prevented the cellular and molecular alterations and improved mechanosensation. VitE deficiency profoundly alters the molecular signature and functional properties of mechanosensitive TH+ DRGN, representing an intriguing shift of the prevailing paradigm from proprioception to mechanical sensation.
AB - Ninety percent of Americans consume less than the estimated average requirements of dietary vitamin E (vitE). Severe vitE deficiency due to genetic mutations in the tocopherol transfer protein (TTPA) in humans results in ataxia with vitE deficiency (AVED), with proprioceptive deficits and somatosensory degeneration arising from dorsal root ganglia neurons (DRGNs). Single-cell RNA-sequencing of DRGNs was performed in Ttpa−/− mice, an established model of AVED. In stark contrast to expected changes in proprioceptive neurons, Ttpa−/− DRGNs showed marked upregulation of voltage-gated Ca2+ and K+ channels in mechanosensitive, tyrosine-hydroxylase positive (TH+) DRGNs. The ensuing significant conductance changes resulted in reduced excitability in mechanosensitive Ttpa−/− DRGNs. A highly supplemented vitE diet (600 mg dl-α-tocopheryl acetate/kg diet) prevented the cellular and molecular alterations and improved mechanosensation. VitE deficiency profoundly alters the molecular signature and functional properties of mechanosensitive TH+ DRGN, representing an intriguing shift of the prevailing paradigm from proprioception to mechanical sensation.
KW - Molecular Neuroscience
KW - Neuroscience
KW - Transcriptomics
UR - http://www.scopus.com/inward/record.url?scp=85074773149&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85074773149&partnerID=8YFLogxK
U2 - 10.1016/j.isci.2019.10.064
DO - 10.1016/j.isci.2019.10.064
M3 - Article
AN - SCOPUS:85074773149
VL - 21
SP - 720
EP - 735
JO - iScience
JF - iScience
SN - 2589-0042
ER -