Available evidence suggests that patients with PD exhibit neurodegeneration not only in the dopaminergic neurons in SN, but also other brain regions including the cortex. The mechanisms underlying the neurodegenerative process remain elusive. In the present study, we found that the cleavage of Bid and its truncated tBid translocation to the mitochondria are implicated in the TNFRI-mediated signaling pathway in the temporal cortex of PD brains. These findings might provide a mechanistic link to how the death receptor leads to the activation of Bid, the dysfunction of mitochondria, and the consequent activation of caspases in the cortex regions of PD brains (figure e-1).
We previously reported that TNFRI levels are elevated in the cortex from AD brains.25
Here, we found an elevated expression of TNFRI and its adaptor protein, TRADD, in the temporal cortex of parkinsonian brains. All of these suggest a possible association of death receptors with cell death in neurodegenerative disorders. A likely interaction partner for TRADD may be FADD, which can then interact with procaspase-8. Activation of procaspase-8 through self-cleavage leads to a series of downstream events, including activation of procaspase-3 and induction of mitochondrial damage.26,27
Bid is a unique BH3-only molecule of Bcl-2 family,15
which is largely present in cytosol and is involved in the cellular destructive process mediated by TNFRI death receptor. A truncated fragment tBid is generated from a proteolytic digestion at Asp-59, a site with a conserved caspase-8-cleavage sequence.28
Upon the stimulation of a particular death signal, tBid translocates to the mitochondria and induces cytochrome c
This is similar to a previous report showing that cells depleted of Bid by immunoprecipitation are no longer able to induce cytochrome c
Bid-induced cytochrome c
release is mediated by 2 different mechanisms. One is responsible for the initial release of free cytochrome c
in the intermembrane space through a Bak-dependent mechanism. The other causes a dramatic remodeling of mitochondrial cristae, which mobilize cytochrome c
storage. Effects of tBid on the mitochondria may not be limited to the induction of cytochrome c
release, but may include other changes in mitochondrial physiology such as mitochondrial redistribution and loss of mitochondrial ψΔm in the cells.33
This portion of cytochrome c
constitutes the majority (85%) of total release.34
The released cytochrome c
then binds with Apaf-1 to form the apoptosome, a multimeric Apaf-1 and cytochrome c
complex. Only the caspase-9 binding to the apoptosome is able to efficiently cleave and activate downstream executioner caspases such as caspase-3.16,35
These executioner caspases will then cleave intracellular substrates, leading to chromatin condensation and DNA fragmentation. As shown in figure e-1, TNFRI can directly activate caspase-3 through caspase-8. This might be due to the amplification of caspase activation and the involvement of additional mitochondrial dysfunction.
Our finding demonstrated that Bid is largely activated in the neurons of the temporal cortex from patients with PD as well as the activation of the entire TNFRI-Bid death signaling pathway in the cortex relevant to nonmotor PD. The results are similar to the observation of TNFRI-engaged hepatocyte apoptosis in which Bid is required for TNFα- and Fas-induced apoptosis through a mitochondrial pathway.34
Our data might in part explain the possibly emerging cognitive decline associated with cortical pathogenesis in PD.