Caspases and Apoptosis Overview

Caspases and Apoptosis

• Caspases are proteases that cleave specific proteins, leading to controlled cell dismantling.
• Initiator caspases activate effector caspases, responsible for degrading the cell.
• Apoptosis is essential for embryonic tissue sculpting and removing excess cells, exemplified in finger and toe formation.
• In the immune system, apoptosis removes unneeded or harmful immune cells, aiding in immune response resolution.
• Dysregulated apoptosis contributes to diseases; excessive apoptosis is linked to degenerative diseases, while insufficient apoptosis can lead to cancer and autoimmune disorders.
• Cancer cells often evade apoptosis, leading to uncontrolled proliferation; therapies aim to induce apoptosis in these cells.

Necroptosis

• Necroptosis is a regulated cell death form, distinct from uncontrolled necrosis and apoptosis.
• First defined in 2005, it is characterized by necrotic cell morphology and is triggered by TNFα receptor 1; it can be inhibited by RIPK1 inhibitors.
• ROS are known inducers of necroptosis and it plays a role in delayed ischemic brain injury in mice, which can be prevented by necrostatin-1.

Autophagy

• Autophagy refers to the degradation and recycling of cellular components, helping maintain homeostasis and respond to stress.
• Attributed to its Greek roots, autophagy means "self-eating."
• Pathological mutations in neurodegenerative diseases like Alzheimer's, Parkinson's, Huntington's, and Amyotrophic Lateral Sclerosis (ALS) are linked to autophagy deficits.
• Autophagy is crucial for clearing damaged mitochondria and protein aggregates, impacting neurodegenerative pathology.

Types and Processes of Autophagy

• Macroautophagy, the most studied form, involves the formation of autophagosomes that encapsulate cellular debris for degradation by lysosomes.
• Regulation of autophagy is complex, involving pathways like mTOR that respond to nutrient levels and stress.
• Autophagy functions include the removal of dysfunctional organelles, recycling proteins, and influencing cell differentiation.
• It is often upregulated under stress conditions such as nutrient deprivation and oxidative stress.

Parthanatos

• Parthanatos is characterized by the excessive activation of the PARP-1 enzyme, leading to chromatin condensation and cell death distinct from apoptosis.
• It is implicated in neurodegenerative diseases like Parkinson's and Alzheimer's, stroke, and myocardial infarction.
• Excessive PARP activation causes neuroinflammation and neuronal degeneration, contributing to disease progression.

PARP-1 and Neurodegeneration

• PARP-1 plays a pivotal role in DNA repair, sensing DNA damage, crucial in neurodegenerative diseases linked to aging.
• Activation from oxidative stress leads to decreased NAD+ and ATP levels, causing energy depletion and increased oxidative damage.
• PARP-1 also influences inflammation by affecting transcription factors, worsening neuronal damage during disease progression.
• Excitotoxicity and mitochondrial dysfunction, driven by PARP-1 activation, contribute significantly to neurodegenerative pathology.

Therapeutic Implications

• While PARP inhibitors show promise in neurodegenerative diseases, concerns include potential genome instability due to long-term use.
• New selective inhibitors that can cross the blood-brain barrier (like AG-014699 and AG14361) may help prevent disease progression.
• Research highlights the importance of understanding Parthanatos in conjunction with other forms of cell death for therapeutic interventions in neurodegeneration.