Progressive degeneration of dopaminergic neurons through TRP channel-induced cell death.
Progressive neurodegenerative diseases are among the most frequently occurring aging-associated human pathologies. In a screen for Caenorhabditis elegans mutant animals that lack their normal complement of dopaminergic neurons, we identified two strains with progressive loss of dopaminergic neurons during postembryonic life. Through whole-genome sequencing we show that both strains harbor dominant (d), gain-of-function mutations in the Transient Receptor Potential (TRP) mechanosensory channel trp-4, a member of the invertebrate and vertebrate TRPN-type of the TRP family channels. Gain-of-function mutations in TRP channels have not been previously implicated in dopaminergic neuronal degeneration. We show that trp-4(d) induces cell death in dopamine neurons through a defined, calcium-related downstream pathway.
Center for Organelle Research, University of Stavanger, 4036 Stavanger, Norway, Norwegian Center for Movement Disorders, Stavanger University Hospital, 4011 Stavanger, Norway, Department of Biology and Health Sciences, Pace University, New York, New York 10038, and Department of Biochemistry and Molecular Biophysics, Howard Hughes Medical Institute, Columbia University Medical Center, New York, New York 10032.
Archana
A
Nagarajan
Ye
Y
Ning
Kaja
K
Reisner
Zafir
Z
Buraei
Jan Petter
JP
Larsen
Oliver
O
Hobert
Maria
M
Doitsidou
D000818:Animals; D017173:Caenorhabditis elegans; D029742:Caenorhabditis elegans Proteins / Q000235:genetics / Q000378:metabolism*; D016923:Cell Death / Q000502:physiology*; D059290:Dopaminergic Neurons / Q000378:metabolism / Q000473:pathology*; D009068:Movement / Q000502:physiology; D009154:Mutation; D009410:Nerve Degeneration / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D050052:TRPC Cation Channels / Q000235:genetics / Q000378:metabolism*
D029742:Caenorhabditis elegans Proteins; D050052:TRPC Cation Channels; C489571:TRPC4 ion channel
C. elegans; TRP channels; calcium; cell death; dopaminergic neurons; neurodegeneration