In vivo contributions of BH3-only proteins to neuronal death following seizures, ischemia, and traumatic brain injury

Abstract

The Bcl-2 homology (BH) domain 3-only proteins are a proapoptotic subgroup of the Bcl-2 gene family, which regulate cell death via effects on mitochondria. The BH3-only proteins react to various cell stressors and promote cell death by binding and inactivating antiapoptotic Bcl-2 family members and direct activation of proapoptotic multi-BH domain proteins such as Bax. Here, we review the in vivo evidence for their involvement in the pathophysiology of status epilepticus and contrast it to ischemia and traumatic brain injury. Seizures in rodents activate three potent proapoptotic BH3-only proteins: Bid, Bim, and Puma. Analysis of damage after seizures in mice singly deficient for each BH3-only protein supports a causal role for Puma and to a lesser extent Bim but, surprisingly, not Bid. In ischemia and trauma, where core aspects of the pathophysiology of cell death overlap, multiple BH3-only proteins are also activated and Bid has been shown to be required for neuronal death. The findings suggest that while each neurologic insult activates multiple BH3-only proteins, there may be specificity in their functional contribution. Future challenges include evaluating the remaining BH3-only proteins, explaining different causal contributions, and, if possible, exploring neurologic outcomes in mouse models deficient for multiple BH3-only proteins.

Figure 1

Molecular structures of Bid, Bim, and Puma. Cartoon showing mus musculus structural features of each Bcl-2 homology domain 3 (BH3)-only protein (Sources: NCBI and uniprot.org and the cited literature in this review). Included are sequence length, estimated molecular weights, and annotations for some of the proposed phosphorylation sites (S, serine residues), and for Bid, posttranslational modification by cleavage and N-myristoylation (G, glycine residue).

Figure 2

Schematic of the possible molecular pathways leading to Bcl-2 homology domain 3 (BH3)-only protein activation. Cartoon showing some of the various factors triggered by seizures, ischemia, and traumatic brain injury (TBI) in neurons and how these may result in activation of Bid, Bim, and Puma. These include phosphatases such as PTEN and calcineurin and stress-activated protein kinases such as c-Jun N-terminal kinase (JNK), which can phosphorylate or upregulate Bim, proteases that can cleave and activate Bid, and various transcription factors that can upregulate Bim and/or Puma. Casp8, caspase-8; ER, endoplasmic reticulum.

Figure 3

Cartoon representation of the importance of the three potently proapoptotic Bcl-2 homology domain 3 (BH3)-only proteins in each model. Bid, Bim, and Puma are activated in ischemia and seizure, although for traumatic brain injury (TBI) there are data only for Bid. Black circle denotes evidence for activation and that the gene-deficient animal (KO) is protected against neuronal death. Grey circle denotes evidence for the BH3-only protein is activated but the knockout mouse was not protected or where further validation will be needed. White circle denotes no evidence yet for activation of the BH3-only protein. ER, endoplasmic reticulum.