Calcium-Mediated Dopaminergic Neuron Loss Caused by TRP Channel Mutations
Nagarajan A, Ning Y, Reisner K, Buraei Z, Larsen JP, Hobert O, Doitsidou M. Progressive degeneration of dopaminergic neurons through TRP channel-induced cell death. J Neurosci 2014;34(17):5738-5746. doi: 10.1523/JNEUROSCI.4540-13.2014.
Background: Dopaminergic neurodegeneration underlies several human disorders, yet the genetic mechanisms that initiate and propagate neuronal loss remain poorly understood. Calcium dysregulation is a common feature of many neurodegenerative conditions, and members of the transient receptor potential (TRP) channel family have been implicated in cellular calcium homeostasis. However, mutations in TRP channels have not previously been shown to directly cause dopaminergic neuron degeneration.
Hypothesis: This study hypothesized that mutations in the trp-4 gene, which encodes a mechanosensitive TRP channel in Caenorhabditis elegans, lead to progressive dopaminergic neuron degeneration through calcium-dependent mechanisms.
Methods: The authors performed an unbiased forward genetic screen for mutants with progressive dopaminergic neuron loss, mapped mutations using whole-genome sequencing, and conducted behavioral and pharmacological analyses. Dopaminergic integrity was visualized using GFP reporters, and locomotor activity was quantified with WormLab.
Results: Two independent mutations, ot337 and ot477, were identified as gain-of-function alleles of trp-4, causing semidominant, progressive degeneration of head dopaminergic neurons. Degeneration was dopamine-independent, exhibited necrotic morphology, and was not suppressed by apoptotic pathway mutations. Chelation of cytoplasmic calcium or inhibition of endoplasmic reticulum calcium release (via crt-1, itr-1, unc-68, or dantrolene treatment) significantly suppressed neuronal loss.
Conclusions: Gain-of-function mutations in the TRP-4 channel induce calcium-mediated necrotic death of dopaminergic neurons in C. elegans. This model establishes TRP channel–related calcium dysregulation as a potential mechanism contributing to neurodegeneration.
