Week 2(2) - Cell death mechanisms of neurodegeneration.pdf

Week 2 (2) Inherited Neurological Disorders (HMG 44110A ) Cell death mechanisms of Neurodegeneration Dr. Merin Thomas [email protected] Office hours : Monday& Wednesday, 3.00pm to 5.00pm...

Week 2 (2) Inherited Neurological Disorders (HMG 44110A ) Cell death mechanisms of Neurodegeneration Dr. Merin Thomas [email protected] Office hours : Monday& Wednesday, 3.00pm to 5.00pm Tuesday & Thursday, 1.00pm to 3.00pm 1  Learning Objectives Apoptosis Necroptosis Autophagy Parthanatos  Introduction Neurodegenerative diseases are caused by interactions of genetic factors and environmental. These disorders share common features, like excitotoxicity, synaptic dysfunction, misfolded protein aggregation, reactive oxidative stress (ROS), mitochondrial deficits, dysregulation of intracellular calcium. Introduction  Introduction Disrupted cell functions together with aging-induced accumulation of DNA damage and oxidative stress gradually crush the self-defense system including the protein quality control system (for example, ubiquitin and autophagy) and others, leading to a shift in life-death balance ending in programmed cell death (PCD). It is likely that multiple cell death pathways are involved in the cell loss in neurodegenerative diseases and in experiment models of Introduction neurodegeneration.  Introduction Survival or death balance and major path to death (how to die) of cells depend on the source, duration, and dose of different stressors, as well as the type, previous challenges, and metabolic conditions of the cell. Several types of cell death including apoptosis, necrosis, autophagy, and parthanatos may be involved in neurodegeneration. We will briefly discuss apoptosis,Introduction necroptosis, autophagy and focus on parthanatos and their involvement and therapeutic potential in neurodegenerative diseases. Apoptosis  Cell Death in Neurodegeneration - Apoptosis Apoptosis is the most studied and well-known form of programmed cell death (PCD), which is found in both development and diseases. Apoptosis is an irreversible process with caspase activation committing a cell to death and the engulfment genes serving the purpose of dead cell removal. Apoptosis describes the orchestrated collapse of a cell characterized by membrane blebbing, cell shrinkage, condensation of chromatin, and fragmentation of DNA followed by rapid engulfment of the corpse by neighboring cells.  Cell Death in Neurodegeneration - Apoptosis There are markers of apoptosis in postmortem tissues of patients, as well as in cell and animal models of neurodegenerative disorders, including Alzheimer’s disease (AD), Huntington’s disease (HD), Parkinson’s disease (PD), and amyotrophic lateral sclerosis (ALS). It is worth noting that certain cell death-related phenomenon may accompany a cell death process while the final execution is carried out by a different cell death mechanism.  Cell Death in Neurodegeneration - Apoptosis Reactive oxygen species (ROS), DNA damage, loss of mitochondria membrane potential, and aggregation of misfolded proteins are all common features associated with most neurodegenerative disorders and major forms of neuronal death. On the other hand, inhibiting cell death by a pan caspases blocker, usually results in delayed death by autophagy or necrosis. Extra caution needs to be taken when classifying a certain type of death as apoptosis. Cell Death in Neurodegeneration – Apoptosis Characteristics 1. Cellular Regulation: Apoptosis is a controlled process that is regulated by a complex interplay of genes and signaling pathways. It is essential for maintaining tissue homeostasis by eliminating damaged, infected, or surplus cells. 2. Morphological Changes: Cells undergoing apoptosis exhibit distinct morphological changes, including cell shrinkage, chromatin condensation, and the formation of membrane-bound apoptotic bodies. These apoptotic bodies contain cell components and are efficiently phagocytosed by neighboring cells or immune cells, preventing inflammation. Cell Death in Neurodegeneration – Apoptosis Characteristics 3. Cell Signaling: Apoptosis can be initiated through two main pathways: the intrinsic (mitochondrial) pathway and the extrinsic (death receptor) pathway. The intrinsic pathway is activated by intracellular stress signals, such as DNA damage or protein misfolding, and it involves the release of cytochrome c from mitochondria. The extrinsic pathway is activated by the binding of death ligands to cell surface death receptors. Cell Death in Neurodegeneration – Apoptosis Characteristics 4. Caspases: Central to apoptosis are a group of enzymes called caspases. Caspases are proteases that cleave specific cellular proteins, leading to the controlled dismantling of the cell. Initiator caspases are activated early in the process and trigger the activation of effector caspases, which carry out the final steps of cell degradation. Cell Death in Neurodegeneration – Apoptosis Characteristics 5. Role in Development: Apoptosis is critical during embryonic development to shape and sculpt tissues and organs. It helps to remove excess cells and define tissue boundaries. For example, the formation of fingers and toes during development involves apoptosis between the digits. 6. Immune System: Apoptosis plays a role in regulating the immune system by eliminating immune cells that are no longer needed or have become potentially harmful. It also contributes to the resolution of immune responses. Cell Death in Neurodegeneration – Apoptosis Characteristics 7. Pathological Conditions: Dysregulation of apoptosis can lead to various diseases. For instance, too much apoptosis is associated with degenerative diseases, while too little apoptosis can lead to cancer, autoimmune diseases, and certain viral infections. 8. Cancer and Therapeutics: Cancer cells often evade apoptosis, allowing them to proliferate uncontrollably. Many cancer treatments, such as chemotherapy and radiation therapy, work by inducing apoptosis in cancer cells. Developing drugs that selectively induce apoptosis in cancer cells is an active area of research. Necroptosis  Cell Death in Neurodegeneration – Necroptosis Necroptosis is a regulated form of cell death that shares some similarities with necrosis, a more chaotic and uncontrolled type of cell death, but it is still distinct from apoptosis, which is another well- regulated form of cell death. Necroptosis has gained attention in recent years as an important cellular process involved in various physiological and pathological conditions. Necroptosis was first defined in 2005 as a regulated form of non- apoptotic cell death with necrotic cell morphology, triggered by TNFα receptor 1 (TNFR1) and can be inhibited by receptor-interacting protein kinase 1 (RIPK1) inhibitor necrostatin 1 (Nec-1).  Cell Death in Neurodegeneration – Necroptosis Besides death receptor activators, such as TNF, ROS have also been shown to promote necroptosis. Necroptosis has been shown to contribute to delayed mouse ischemic brain injury, which can be inhibited by necrostatin1. A group recently detected activation of RIPK1 and RIPK3 in multiple sclerosis (MS) patient cortical samples and also showed that RIPK1 inhibitor Nec-1s reduced oligodendrocyte death in two MS animal models.  Cell Death in Neurodegeneration – Necroptosis Characteristics 1. Regulated Cell Death: Necroptosis is a programmed and regulated form of cell death, unlike necrosis, which is typically uncontrolled and associated with cell damage and inflammation. 2. Initiation: Necroptosis is initiated in response to specific signals, often when apoptosis is blocked or inhibited. In some cases, it can be triggered by extracellular factors or intracellular damage.  Cell Death in Neurodegeneration – Necroptosis Characteristics 3. Mechanisms: The molecular mechanisms of necroptosis involve a family of proteins called receptor-interacting protein kinases (RIPKs), particularly RIPK1 and RIPK3. When activated, RIPK1 and RIPK3 form a complex known as the necrosome, which leads to the execution of necroptosis. 4. Morphological Features: Necroptosis is characterized by the swelling of organelles, plasma membrane rupture, and the release of intracellular contents. This release can induce inflammation and an immune response in the surrounding tissues.  Cell Death in Neurodegeneration – Necroptosis Characteristics 5. Inflammatory Response: Necroptosis is often associated with the release of damage-associated molecular patterns (DAMPs), which can trigger inflammation and immune responses. This inflammatory aspect distinguishes necroptosis from apoptosis, which is typically immunologically silent. 6. Roles in Disease: Necroptosis has been implicated in various diseases, including neurodegenerative diseases, ischemic injury, inflammatory disorders, and viral infections. In some cases, blocking or modulating necroptosis has shown promise as a potential therapeutic approach.  Cell Death in Neurodegeneration – Necroptosis Characteristics 7.Therapeutic Potential: Understanding and manipulating necroptosis pathways hold potential for the development of novel therapeutic strategies. Targeting necroptosis could be valuable in conditions where excessive cell death and inflammation are problematic. 8. Necroptosis in Cancer: While necroptosis is generally considered a cell death pathway, in some contexts, it can play a role in suppressing tumor growth. Inducing necroptosis in cancer cells has been explored as a potential anticancer strategy. Autophagy  Cell Death in Neurodegeneration – Autophagy Autophagy is a cellular process that involves the degradation and recycling of cellular components and organelles. The term "autophagy" is derived from the Greek words "auto" (self) and "phagy" (eating), which reflect the process of a cell "eating" its own components. This process plays a critical role in maintaining cellular homeostasis, removing damaged or unwanted cellular materials, and responding to various stress conditions.  Cell Death in Neurodegeneration – Autophagy Several pathological mutations of proteins in AD, PD, HD, and ALS are linked to deficits of autophagy, such as substrate recognition, lysosome acidification, trafficking, and membrane permeabilization. Autophagy plays important role in cleaning up damaged mitochondria and aggregated proteins and thus contributes to neurodegenerative pathology. Defects in autophagy primarily play a role in neurodegeneration, but autophagy itself can also be involved in several forms of cell death. Cell Death in Neurodegeneration – Autophagy Characteristics 1. Types of Autophagy: There are several types of autophagy, but the most well-known and extensively studied is macroautophagy. Other types include microautophagy and chaperone-mediated autophagy. 2. Process: In macroautophagy, a double-membraned structure called an autophagosome forms around cellular cargo, such as damaged organelles or protein aggregates. The autophagosome then fuses with lysosomes, which contain enzymes capable of breaking down the cargo. This results in the degradation and recycling of the enclosed material. Cell Death in Neurodegeneration – Autophagy Characteristics 3. Regulation: Autophagy is a highly regulated process. Various signaling pathways, including the mTOR (mammalian target of rapamycin) pathway, play a role in initiating or inhibiting autophagy in response to nutrient availability and stress conditions. 4. Physiological Roles: Autophagy serves several important functions in the cell. It helps remove damaged or dysfunctional organelles, clears misfolded or aggregated proteins, recycles cellular components, and is involved in cell differentiation and development Cell Death in Neurodegeneration – Autophagy Characteristics 5. Stress Response: Autophagy is often upregulated in response to various forms of stress, such as nutrient deprivation, oxidative stress, and infection. It allows cells to survive under adverse conditions by breaking down and recycling cellular components to provide essential nutrients. 6. Role in Disease: Dysregulation of autophagy is associated with a range of diseases, including neurodegenerative disorders like Alzheimer's and Parkinson's disease, cancer, and metabolic disorders. In some cases, autophagy may either promote or inhibit disease progression, depending on the context. Cell Death in Neurodegeneration – Autophagy Characteristics 7. Cancer: Autophagy can have a dual role in cancer. It can promote tumor survival by providing nutrients and mitigating stress, but it can also suppress tumor initiation by removing damaged cells and maintaining genomic stability. The role of autophagy in cancer is complex and context-dependent. 8. Therapeutic Implications: Autophagy modulation is an active area of research for therapeutic interventions. In some cases, enhancing autophagy may be beneficial, while in others, inhibiting autophagy may be desirable, depending on the specific disease and circumstances. Parthanatos  Cell Death in Neurodegeneration – Parthanatos Parthanatos is a type of programmed cell death that is distinct from apoptosis, necroptosis, and autophagy. Parthanatos, previously known as PARP-1-dependent cell death, is the second most studied form of cell death It is characterized by the activation of a specific cell death pathway involving the enzyme poly(ADP-ribose) polymerase (PARP) and the subsequent release of apoptosis-inducing factor (AIF) from mitochondria. Parthanatos is implicated in various pathological conditions, particularly in the context of neurodegenerative diseases and ischemic injury.  Cell Death in Neurodegeneration – Parthanatos Characteristics 1. PARP Activation: Parthanatos is initiated by the hyperactivation of poly(ADP-ribose) polymerase (PARP), a nuclear enzyme involved in DNA repair and genomic stability. In response to DNA damage, PARP catalyzes the synthesis of poly(ADP-ribose) (PAR) chains as a signaling molecule. 2. Excessive PAR Formation: In Parthanatos, there is excessive PAR formation due to persistent DNA damage or cellular stress. This hyperactivation of PARP consumes cellular energy resources, such as NAD+ (nicotinamide adenine dinucleotide), leading to energy depletion.  Cell Death in Neurodegeneration – Parthanatos Characteristics 3. Release of AIF: Excessive PAR formation triggers the translocation of apoptosis-inducing factor (AIF) from the mitochondria to the nucleus. AIF then causes chromatin condensation and DNA fragmentation, leading to cell death. 4. Distinct from Apoptosis: Parthanatos is distinct from apoptosis in terms of its molecular mechanisms and morphological features. While apoptosis is characterized by cell shrinkage and the formation of apoptotic bodies, Parthanatos is characterized by chromatin condensation and nuclear changes.  Cell Death in Neurodegeneration – Parthanatos Characteristics 5. Role in Disease: Parthanatos has been implicated in various neurodegenerative diseases, such as Parkinson's disease and Alzheimer's disease, as well as in conditions like stroke and myocardial infarction. In these contexts, the excessive activation of PARP and the subsequent cell death contribute to tissue damage and degeneration. 6. Therapeutic Implications: Research into Parthanatos has led to the development of potential therapeutic strategies aimed at blocking or modulating the pathway. Inhibitors of PARP have been investigated as potential treatments for diseases where Parthanatos is implicated. Major forms of cell death found in neurodegenerative diseases  Cell Death in Neurodegeneration – Parthanatos Several key components are involved in the process of Parthanatos PARP-1 - Poly(ADP-ribose) polymerase 1 (PARP-1) is the major isoform of a family of nuclear enzymes with multiple regulatory function PARG - Poly(ADP-ribose) glycohydrolase (PARG) is the major enzyme responsible for the catabolism of poly(ADP-ribose). The protein is found in many tissues and may be subject to proteolysis generating smaller, active products Components of Parthanatos PAR - Poly(ADP-ribose) AIF - apoptosis-inducing factor Iduna - a poly(ADP-ribose) (PAR)-dependent E3 ubiquitin ligase that regulates DNA damage  Cell Death in Neurodegeneration – Parthanatos Some research suggests that the Parthanatos pathway may be involved in the pathogenesis of neurodegenerative diseases, particularly in the context of DNA damage and cell death. The excessive activation of PARP-1 and the subsequent initiation of Parthanatos can lead to neuroinflammation and cell death in neurons, contributing to the progression of certain neurodegenerative diseases. Parthanatos and Neurodegenerative Diseases The exact role of Parthanatos in these diseases, as well as potential therapeutic interventions targeting this pathway, is an active area of research, and there have been significant developments in this field.  Cell Death in Neurodegeneration – Parthanatos PARP-1 - CHARACTERISTICS PARP-1 is the most abundant and best characterized member of the 17 mammalian PARP family proteins. PARP-1 is responsible for production of more than 90% of cellular PAR polymers. Under physiological conditions, PARP-1 activity remains at a low level, Parthanatos and Neurodegenerative Diseases but can increase up to 500-fold in a few seconds when sensing mild DNA damage.  Cell Death in Neurodegeneration – Parthanatos PARP-1 - CHARACTERISTICS Mild or moderate stresses usually lead to PARP-1 activation that results in DNA repair and transcription regulation to restore genome stability, degrade oxidized or damaged proteins, and maintain homeostasis. On the other hand, hyperactivation of PARP- 1 by severe or sustained stresses causes cell death programs, such as parthanatos. Parthanatos and Neurodegenerative Diseases  Cell Death in Neurodegeneration – Parthanatos PARP-1 and Neurodegeneration PARP-1 has emerged as a major death regulator in both acute neuronal injury and neurodegenerative disorders. Oxidative stress, is one of the most important common features of neurodegenerative disorders and aging diseases, which is able to activate PARP-1. Involvement of PARP-1 has been found in human patient brains, as well as cellular and rodent models of stroke, trauma, spinal cord Parthanatos and Neurodegenerative Diseases injury, AD, PD, HD, MS, and ALS.  Cell Death in Neurodegeneration – Parthanatos PARP-1 and Neurodegeneration Furthermore, PARP inhibitors and genetic deletion of PARP-1 are strongly neuroprotective in NO-mediated toxicity, NMDA excitotoxicity, as well as experiment models of ischemic injury, traumatic brain injury, AD, HD, and PD. Parthanatos and Neurodegenerative Diseases  Cell Death in Neurodegeneration – PARP-1 and Neurodegeneration In the context of neurodegeneration, PARP-1 has been the subject of research due to its involvement in several mechanisms that contribute to neurodegenerative diseases. Here's an overview of the connection between PARP-1 and neurodegeneration: 1. DNA Repair: PARP-1 is primarily known for its role in DNA repair. It senses DNA damage, such as single-strand breaks, and facilitates the repair process. In neurodegenerative diseases, PARP-1 and Neurodegeneration especially those associated with aging, accumulated DNA damage and impaired DNA repair mechanisms can lead to neuronal dysfunction and cell death.  Cell Death in Neurodegeneration – PARP-1 and Neurodegeneration 2. Oxidative Stress: PARP-1 is activated in response to oxidative stress, which is a common feature of many neurodegenerative disorders, including AD, PD, and Amyotrophic Lateral Sclerosis (ALS). Overactivation of PARP-1 can decrease cellular NAD+ and ATP levels, leading to energy depletion and further oxidative damage. 3. Inflammation: PARP-1 can also modulate inflammation by regulating PARP-1 and Neurodegeneration the activity of transcription factors such as NF-κB. Inflammatory processes are implicated in the pathogenesis of several neurodegenerative diseases, and PARP-1's involvement in promoting inflammation can worsen neuronal damage.  Cell Death in Neurodegeneration – PARP-1 and Neurodegeneration 4. Excitotoxicity: In conditions like ischemic stroke or traumatic brain injury, excessive activation of PARP-1 can lead to neuronal death through Parthanatos, which involves mitochondrial dysfunction, release of mitochondrial DNA, and cell death. 5. Mitochondrial Dysfunction: PARP-1 activation can lead to mitochondrial dysfunction, which is a central feature in the pathogenesis of many neurodegenerative diseases. Mitochondrial PARP-1 and Neurodegeneration dysfunction contributes to energy deficits and the generation of reactive oxygen species (ROS), further damaging neurons.  Cell Death in Neurodegeneration – PARP-1 and Neurodegeneration PARP inhibitors for neurodegenerative diseases There are concerns about the long-term use of PARP inhibitors for chronic neurodegenerative diseases due to the potential side effects including genome instability. However, PARP-1 knockout mice are viable and are resistant to numerous toxic stimuli, which suggests that PARP family members may also play a role in DNA repair and maintaining genome stability. Nevertheless, new potent selective PARP-1 inhibitors, which cross blood– brain barrier, such as AG-014699 and AG14361, could be beneficial in preventing or delaying neurodegenerative disease progression.  Cell Death in Neurodegeneration – PARP-1 and Neurodegeneration In summary, Parthanatos plays important roles in excitotoxicity, acute neurological diseases such as ischemic stroke and traumatic injury, and neurodegenerative disorders including PD, AD, HD, ALS, and MS. Although cell death itself is the endpoint event at the late stage of neurodegeneration, pharmacological inhibitors and genetic deletions of the mediators in cell death show beneficial effects in cellular and animal models of neurodegenerative diseases, indicating that preventing or reducing cell loss are still promising therapeutic interventions that could probably slow down the disease progress.  Cell Death in Neurodegeneration – PARP-1 and Neurodegeneration Further investigation of parthanatos-signaling mechanisms and roles of Parthanatos mediators in different neurologic and neurodegenerative disorders is essential. It will also be important to understand the interactions between Parthanatos and other major forms of cell death in neurodegenerative diseases.  REFERENCES Beart, P., Robinson, M., Rattray, M., & Maragakis, N. J. (2017). Neurodegenerative diseases: Pathology, Mechanisms, and Potential Therapeutic Targets. Springer.