*2.2. Cell Death Regulation in Response to Neuronal Stress*

The signaling of the c-Jun amino terminal kinase (JNK) pathway induces traumatic responses that lead to the death of neurons. The role of the JNK signaling pathway has been characterized as the functioning of neurons, including responses that mediate neuronal injury [35]. Another protein, namely, dual leucine zipper kinase (DLK), regulates

JNK signaling and upstream neuronal functioning. It is mainly triggered by neurotrophic growth factors, oxidative stress, injuries associated with neurons and axons, and misfolded proteins [36]. DLK proteins lead to JNK phosphorylation and translocate to the nucleus. This phosphorylation further leads to transcriptional stress and culminates in CNS apoptosis. The DLK proteins control the degeneration of neurons in the developmental phase, but if uncontrolled it progresses to conditions of injury in neurons and neurodegeneration [37].

The neuronal cells that lack signaling by DLK proteins fail to generate a normal transcriptional injury response and further attenuate the activation of caspases, and hence, are strongly protected from destruction upon exposure to stress [38]. The activity of protein kinase R-like endoplasmic reticulum kinase (PERK) can be hampered by the signaling of DLK proteins to prevent the phosphorylation and translation of eukaryotic initiation factor-2α in neurons post-acute injury [39]. The signaling of PERK is a component of unfolded protein responses and its activation by DLK proteins significantly demonstrates its participation in the destruction of neurons. Therefore, the signaling of proteins like DLK, JNK, and PERK induces stress responses that further lead to the signaling of pathways, leading to cell death [40].

### *2.3. Programmed Destruction of Neurons by the Degeneration of Axons*

The degeneration of axons can be mainly portrayed by forfeited connectivity in neurons [41]. This is the earliest clinical feature that has been discovered in most neurodegenerative diseases [42]. The degeneration of axons is a dynamic activity that depends upon the signaling of local axons and their transcriptional regulation within the body of neuron cells [43]. Axon degeneration, in conjunction with the apoptosis of neurons, further aggravates the condition. Several pathways such as the withdrawal of trophic factors, DLK/JNK signaling pathways [44], and several chemotherapeutic compounds appear to be involved in axonal degeneration, whereas the DLK pathway is considered to be the governing pathway that leads to axonal degeneration by activating the signaling of caspase proteins and ultimately neuronal cell death [45]. Figure 2 briefly mentions all the factors that are involved in the pathway of cell death via processes of neuronal apoptosis, the formation of a cascade of proteolysis that induces mitochondrial stress and damage, and the signaling of various proteins such as c-Jun amino terminal kinase (JNK) and dual leucine zipper kinase (DLK), which leads to translocation to the nucleus and ultimately causes cell death.

**Figure 2.** The factors that are involved in the pathways of cell death. Legend: JNK—c-Jun amino-terminal kinase; DLK—dual leucine zipper kinase.

Apart from the mechanisms stated above, there are several other factors that lead to neuronal cell death in diseases, such as protein homeostasis, [20] mitochondrial dysfunction, neuroinflammation, selective vulnerability, and linking of initiators and executioners of neurodegenerative diseases. All these factors run parallel and induce stress intracellularly in neurons, which leads to their death and chronic neurodegenerative disorders. These are also guided by accretion of the proteins that have misfolded or are defective in the endolysosomal system and oxidative stress.

The most common trait involved in the etiology of neurological disorders like Alzheimer's disease and Parkinson's disease includes the aggregation of toxic misfolded proteins, which leads to synaptic dysfunction and the destruction of neurons [46] For instance, the extracellular β-amyloid plaques observed in Alzheimer's disease in conjunction with intracellular neurofibrillary tangles formed by the hyperphosphorylation of the tau protein is the contributing factor in the pathophysiology of Alzheimer's disease [47]. The precise mechanism that triggers the conversion of normal proteins into misfolded proteins is lucid; however, the misfolded proteins recruit healthy proteins into lethal oligomers and accelerate their aggregation. These aggregated proteins sequesters from their colony and prevent the functioning that is necessary for their survival [48].

During normal physiological conditions, proteins, with the help of endoplasmic reticulum chaperones, are folded into their native form while the misfolded proteins are engulfed by autophagosomes, lysosomes, and proteosomes, a process called protein homeostasis. In conditions of stress, the misfolded proteins are generated in bulk and their aggregation leads to toxic functioning due to loss of endogenous functioning, which drives neuron cell death. Protein homeostasis is a critical process that governs the overall health of neurons. Mitochondrial dysfunction and neuroinflammation also lead to cytotoxicity in the brain and play a major role in the pathophysiology of neurodegenerative diseases. These processes mainly include the release of cytotoxic inflammatory cytokines in the brain, which causes phagocytosis of damaged neurons [49].

A selective region in brain and subsets of neurons that are highly exposed to cytotoxic agents lead to disease progression, a phenomenon called selective vulnerability. For instance, the pyramidal neurons in the entorhinal cortex region of the brain are initially targeted in Alzheimer's disease. Hence, different pathophysiology in different regions of the brain mediates neurodegeneration, and thorough knowledge of neuron dysfunction processes and cell death can open opportunities for the development of more targeted therapies and enhance the quality of life of the affected populations.
