Increased TRPC5 glutathionylation contributes to striatal neuron loss in Huntington’s disease

Abstract

Aberrant glutathione or Ca(2+) homeostasis due to oxidative stress is associated with the pathogenesis of neurodegenerative disorders. The Ca(2+)-permeable transient receptor potential cation (TRPC) channel is predominantly expressed in the brain, which is sensitive to oxidative stress. However, the role of the TRPC channel in neurodegeneration is not known. Here, we report a mechanism of TRPC5 activation by oxidants and the effect of glutathionylated TRPC5 on striatal neurons in Huntington's disease. Intracellular oxidized glutathione leads to TRPC5 activation via TRPC5 S-glutathionylation at Cys176/Cys178 residues. The oxidized glutathione-activated TRPC5-like current results in a sustained increase in cytosolic Ca(2+), activated calmodulin-dependent protein kinase and the calpain-caspase pathway, ultimately inducing striatal neuronal cell death. We observed an abnormal glutathione pool indicative of an oxidized state in the striatum of Huntington's disease transgenic (YAC128) mice. Increased levels of endogenous TRPC5 S-glutathionylation were observed in the striatum in both transgenic mice and patients with Huntington's disease. Both knockdown and inhibition of TRPC5 significantly attenuated oxidation-induced striatal neuronal cell death. Moreover, a TRPC5 blocker improved rearing behaviour in Huntington's disease transgenic mice and motor behavioural symptoms in littermate control mice by increasing striatal neuron survival. Notably, low levels of TRPC1 increased the formation of TRPC5 homotetramer, a highly Ca(2+)-permeable channel, and stimulated Ca(2+)-dependent apoptosis in Huntington's disease cells (STHdh(Q111/111)). Taken together, these novel findings indicate that increased TRPC5 S-glutathionylation by oxidative stress and decreased TRPC1 expression contribute to neuronal damage in the striatum and may underlie neurodegeneration in Huntington's disease.

Glutathione depletion activates the yeast vacuolar transient receptor potential channel, Yvc1p, by reversible glutathionylation of specific cysteines

“…Although no cysteine is conserved among mammalian TRPs, all three cysteines are present in the N-terminal cytoplasmic region, similar to what has been observed with the N-terminal cysteines of mammalian TRPs (TRPA1, TRPV1, and TRPC5), which have also been shown to be redox sensitive (Salazar et al. , 2008; Hong et al. , 2015).…”

Crosstalk between calcium and reactive oxygen species signaling in cancer

“…ROS/RNS have been shown to regulate a number of TRPC family members, including TRPC3, 4 and 5, which are activated following oxidative stress in a number of cell lines [153-155]. While there are studies to show the importance of TRPC channel activity in regulating cancer cell migration, proliferation, epithelial-to-mesenchymal transition, angiogenesis and chemoresistance [109, 156-161], studies have not focused on the redox regulation of these in the context of an enhanced ROS tumor cell milieu or in response to ROS-generating conditions emanating from the tumor microenvironment. This is clearly an area that requires further attention.…”

Emerging pathways driving early synaptic pathology in Alzheimer's disease

“…Conversely, FAD PS2 mutations have been found to inhibit TRPC6 [81] and thus may contribute to the demise of synapses that are crticial for syanaptic and behavioral plasticity. In other neurodegenerative diseases such as Huntington’s disease, TRPC5 function is closely linked to cell death [63], further implicating the TRPC channel class broadly in neurodegenerative disorders.…”