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Published on: April 24, 2021
Targeting Bid to prevent programmed cell death in neurons
1Pharmaceutical Biology-Biotechnology, Department of Pharmacy, Ludwig-Maximilians-University, Butenandtstrasse 5-13, Building D, D-81377 Munich, Germany. carsten.culmsee@cup.uni-muenchen.de
Abstract:
Sustained progression of neuronal cell death causes brain tissue loss and subsequent functional deficits following stroke or central nervous system trauma and in neurodegenerative diseases. Despite obvious differences in the pathology of these neurological disorders, the underlying delayed neuronal demise is carried out by a common biochemical cell death programme. Mitochondrial membrane permeabilization and subsequent release of apoptotic factors are key mechanisms during this process. Bcl-2 family proteins, e.g. the pro-apoptotic Bid, Bax or Bad and the antiapoptotic Bcl-2, Bcl-X(L), play a crucial role in the regulation of this mitochondrial checkpoint in neurons. In particular, cleavage of cytosolic Bid and subsequent mitochondrial translocation have been detected in many paradigms of neuronal cell death related to acute or chronic neurodegeneration. The current review focuses on the emerging role of Bid as an integrating key regulator of the intrinsic death pathway that amplifies caspase-dependent and caspase-independent execution of neuronal apoptosis. Therefore pharmacological inhibition of Bid provides a promising therapeutic strategy in neurological diseases where programmed cell death is prominent.
Insights
Bid protein plays a key role in neuronal cell death pathways common to stroke, trauma, and neurodegenerative diseases. Inhibiting Bid offers a promising therapeutic strategy for these neurological conditions.
Area of Science:
- Neuroscience
- Molecular Biology
- Pathology
Background:
- Neuronal cell death contributes to functional deficits in stroke, CNS trauma, and neurodegenerative diseases.
- A common biochemical cell death program, involving mitochondrial permeabilization and apoptotic factor release, underlies delayed neuronal demise.
- Bcl-2 family proteins, including Bid, regulate this critical mitochondrial checkpoint in neurons.
Purpose of the Study:
- To review the role of Bid in the intrinsic pathway of neuronal apoptosis.
- To highlight Bid's function as an integrating regulator amplifying both caspase-dependent and -independent neuronal death.
- To discuss the therapeutic potential of inhibiting Bid in neurological diseases.
Main Methods:
- Review of existing literature on neuronal cell death mechanisms.
- Focus on the intrinsic apoptotic pathway and the role of Bcl-2 family proteins.
- Analysis of Bid cleavage, mitochondrial translocation, and its impact on neuronal apoptosis.
Main Results:
- Cleavage and mitochondrial translocation of Bid are observed in various neuronal cell death paradigms.
- Bid acts as a central regulator, amplifying the execution phase of neuronal apoptosis.
- Bid integrates signals leading to both caspase-dependent and caspase-independent neuronal death.
Conclusions:
- Bid is a crucial integrator of the intrinsic neuronal death pathway.
- Pharmacological inhibition of Bid presents a promising therapeutic avenue for neurological disorders characterized by programmed cell death.
- Targeting Bid may offer a unified strategy for treating diverse neurodegenerative conditions.
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