Apoptosis

Neuronal survival requires environmental signals, which can be received from multiple sources:
- Paracrine: from neighboring cells
- Afferent-derived: from cells innervating the neuron
- Glial-derived: interactions between neurons and glial cells are vital for their survival and differentiation
- Target-derived: these factors influence the neurons’ fates as well
Overall, the Neurotrophic Hypothesis implies that neurons depend on compounds, called neurotrophic factors, for growth and maintenance.

Synthesis: Neurotrophins are synthesized as approximately 250 amino acid precursors (proNGF). They are processed into 120 amino acid mature proteins (mNGF).
Major Families of Neurotrophins:
1. Nerve Growth Factor (NGF)
2. Brain-Derived Neurotrophic Factor (BDNF): ~50% homologous to NGF
3. Neurotrophins NT-3 & NT4/5: These are known to be degraded.

Neurotrophins can be processed inside and/or outside the cell:
1. Inside processing: proNGF can be cleaved by various proteases:
- Furin
- Proconvertases
1. Outside processing: proNGF is released with proteases that generate plasmin, which then cleaves proNGF into its mature form. ProNGF is released from nerve terminals following electrical activity (Barker 2009).

p75NTR: This receptor was the first to be purified and cloned and shows homology with the TNF receptor (TNFR).
Trk Receptors: Tropomyosin receptor kinases consist of the following:
1. Trk A: Binds NGF
2. Trk B: Binds NT4 and BDNF
3. Trk C: Binds NT3
4. p75NTR: A co-receptor for all neurotrophins
- Each receptor has low affinity (some promiscuity) and can form heterodimers with p75, which increases their affinity and specificity (Chao 2003).

p75NTR mediates cell death by being homologous to the TNF receptor family, all of which contain a death domain that activates caspases in the cell death pathway.
It dimerizes with the co-receptor sortilin, promoting apoptosis via caspases when binding to proNGF or proBDNF, which are biologically active and high-affinity ligands for p75NTR (Mohamed & El-Remessy, 2015).

Transition from neurotrophins to cell death involves two pathways:
1. Intrinsic Pathway: Neurotrophic withdrawal from neurons.
2. Extrinsic Pathway: Apoptosis signaling via pro-neurotrophins and p75/sortilin co-receptors.
Both pathways activate distinct apoptosis mechanisms but lead to cell destruction (Mohamed & El-Remessy, 2015).

Programmed Cell Death:
1. A biochemical pathway activated in response to stimuli leading to specific cell destruction.
2. Integral to normal neuronal development, hence termed "programmed."
Apoptosis:
1. Greek meaning "dropping off,” similar to leaves falling in autumn.
2. It is an active cell death pathway not limited to developing organs.
Apoptosis and PCD share similar molecular machinery, often viewed interchangeably.

Necrosis:
- Triggered by acute injury leading to:
- Swelling
- Cell lysis
- Cellular debris left behind
- No activation of the cell death program.
Apoptosis:
- No swelling occurs.
- Key characteristics:
- Chromatin condensation
- DNA fragmentation
- Membrane blebbing
- P-serine flipping onto the outer leaflet (flipase)
- Phagocytosis is activated
Apoptosis is distinct from necrosis due to its controlled and regulated process.

Cell death can be triggered through two primary mechanisms:
1. Intrinsic Factors: Stress pathway.
2. Extrinsic Factors: Death receptor pathway.
Each pathway involves three steps:
1. Arbitration
2. Commitment
3. Execution via caspases (Cory and Adams, 2002).

Caspases are cysteine proteases crucial for apoptosis, known for their cleavage sites at aspartate residues.
Specific caspases play differentiating roles within the apoptosis process, categorized into:
1. Initiator Caspases: Trigger apoptosis.
2. Executioner Caspases: Carry out cell death (including scavenging of cellular components).

Arbitration Group: Divided into two families:
- Pro-apoptotic
- Anti-apoptotic: Defined by Bcl-2 homology (BH1–BH4), with the BH4 domain exclusive to anti-apoptotic members. These domains interact to form oligomers that impact mitochondrial membrane permeability (Opferman & Korsmeyer, 2003).
Cytochrome C Release:
- Triggers pivotal apoptotic mechanisms.
- Initiated by stimuli such as DNA damage, ischemia, oxidative stress, and withdrawal of trophic support.
- Anti-apoptotic proteins block pore formation, while pro-apoptotic proteins promote it.
Apaf-1 and Caspase Activation:
- Binding of cytochrome c to Apaf-1 activates the apoptosome and ensures downstream activation of procaspase-9.
- Apaf-1 acts as an allosteric activator and is essential for forming the apoptosome.

Active caspases function as tetramers consisting of:
- 2 identical large subunits (17-22 kD)
- 2 identical small subunits (10-12 kD)
They interact with caspase substrates leading to cellular destruction (Gupta et al., 2005).

Death Receptor Pathway: Key roles of various death receptors, including:
- FasL: Binds and activates procaspase-8 through adaptor FADD.
- TNF: Engages similar pathways.
Death-Inducing Signaling Complex (DISC) formation is instigated by ligand-receptor binding, leading to caspase activation through island modules (Activate caspase-8).
Bid Protein Role:
- Cleaved by caspase-8, truncated Bid (tBid) enhances cytochrome c release by forming pores in the mitochondrial membrane.
This highlights the interconnectivity between intrinsic and extrinsic pathways in the apoptotic process.

Intrinsic Pathway
- Growth factor withdrawal triggers apoptosis involving AKT pathways and mitochondrial cytochrome c release.
Extrinsic Pathway
- Death receptor signaling leads to DISC formation and eventual caspase activation.
Understanding these pathways is crucial for comprehending how neurotrophins influence neuronal death and survival in various conditions.