✍️ Author: Dr Eleni Christoforidou
🕒 Approximate reading time: 5 minutes
Neurodegenerative diseases, ranging from Alzheimer's to Parkinson's, are characterised by the progressive loss of neuronal function and structure. A quintessential aspect of these diseases is the death of neurons, an irreversible event that culminates in the clinical manifestations of these conditions. This article will delve into the mechanisms behind neuronal cell death in neurodegeneration.
Apoptosis is a form of programmed cell death, and it's a fundamental biological process ensuring the balance between cell birth and death. It's characterised by cell shrinkage, nuclear fragmentation, and the activation of specific proteases called caspases. In neurodegenerative diseases, damaged neurons may undergo apoptosis due to a variety of triggers, including DNA damage, oxidative stress, or the presence of misfolded proteins.
Historically, necrosis was thought to be a form of uncontrolled cell death, in stark contrast to the highly regulated process of apoptosis. It's often a result of extreme physical, chemical, or mechanical injury. In the context of neurodegeneration, however, emerging research suggests that certain forms of necrosis can also be regulated, particularly when associated with mitochondrial dysfunction or calcium overload.
Autophagy, a cellular process that disposes of damaged organelles or misfolded proteins, can be protective for neurons. However, when this system becomes overwhelmed or dysfunctional, it can lead to cell death. Aberrant autophagy has been implicated in diseases like Huntington's and Alzheimer's, where the accumulation of harmful proteins can overload the autophagic process.
While glial cells – including astrocytes and microglia – are vital for supporting neuronal functions, they can become overactive in pathological states. Chronic neuroinflammation, driven by these glial cells, releases pro-inflammatory cytokines and other chemicals toxic to neurons, accelerating their death.
Derived from the name of the Greek god of death, Thanatos, parthanatos is a cell death mechanism distinct from apoptosis and necrosis. It's triggered by overactivation of the enzyme PARP-1 in response to DNA damage. Excessive activation results in the depletion of cellular energy stores, leading to cell death. This mechanism has been observed in conditions such as stroke and Parkinson’s disease.
Understanding the mechanisms of neuronal cell death is pivotal for devising effective therapeutic interventions for neurodegenerative diseases. While the above pathways highlight the main processes, it's worth noting that these mechanisms often overlap, and a single neuron might be affected by multiple death pathways simultaneously. As research progresses, the hope is to harness this knowledge to develop targeted treatments that can prevent or slow down the relentless course of neurodegenerative disorders.