Neurodegeneration is a term widely used in scientific publications, medical texts, and the broad literature – yet, when put under scrutiny, it lacks a clear, universally accepted definition. The most basic definition of neurodegeneration is the progressive, structural, and/or functional decline of neural tissue, regardless of the cause being primarily rooted in the deterioration of neuronal or glial cells, or whether central (CNS) or peripheral (PNS) nervous system is predominantly affected. In a very commonly used, stricter sense, neurodegeneration is limited to neuronal degeneration, i.e., the decay of neurons, rather than neural degeneration, which encompasses both neurons and glial cells.
Historically and clinically, however, the term neurodegenerative diseases are more narrowly demarcated and typically comprise diseases characterized by progressive neurofunctional decline thought to be of neuronal origin within the CNS. Prominent examples of neurodegenerative diseases are Alzheimer’s disease (AD), Parkinson’s disease (PD), Huntington’s disease (HD), or Amyotrophic Lateral Sclerosis (ALS). In contrast, diseases of the PNS caused by neurodegeneration are termed peripheral neuropathies or simply neuropathies.
On the contrary, Multiple Sclerosis (MS) and leukodystrophies are demyelinating diseases characterized by defects in or failure of myelin-forming glia. These are due to either abnormal and degenerating myelin production or the destruction of myelin by toxins or immune attacks. When the myelin sheath, the nerve insulation that allows nerve conduction, is dysfunctional, degeneration of axons and neurons typically follows. The severe symptoms underlying most demyelinating diseases are due to the impairment of neuronal function and decay. This is why MS, often classified as a neurodegenerative disease, further confounds the definition of the term.
Additionally, physical damage (e.g., injury, tumor, ischemia, or stroke) exacerbated by accompanying inflammation, scar tissue formation, and tissue repair mechanisms often result in degeneration of neurons in the affected area. Furthermore, recent research has linked glial impairments with diseases classically thought of as neurodegenerative. The intricate interplay of astroglia, the myelin-forming glia (oligodendrocytes or Schwann cells), and neurons, and their intertwined dependencies to ensure optimal neural and neuronal function renders the distinction between neuronal- and glial-mediated neurodegeneration difficult and often moot.
Nearly all nervous system diseases with neurodegeneration are progressive and lack any prevention therapy or cure. Medical intervention at best halts progression, but it is typically limited to managing symptoms and minor improvements in patients’ wellbeing.
Factors Contributing to Neurodegeneration
Hundreds of neurodegenerative diseases exist, and with a few exceptions, the roots are unknown. Moreover, even when the cause has been identified, the exact cellular mechanism by which the disease is initiated and neurodegeneration is triggered often remains speculative.
A variety of factors can lead to the degeneration of neurons, many of which appear intertwined in neurodegenerative diseases:
Genetic Causes and Risk Factors
A wide variety of rare neurodegenerative diseases exist with defined genetic causes. Mutations disrupt the function of genes vital to neuronal or glial cell biology and lead to the early onset of severe neurological disorders. Other genetic variants pose risk factors, meaning that they increase the likelihood of a spontaneous neurodegenerative disease without directly causing it.
Epigenetics
While rarely directly causative, altered epigenetic regulations such as altered DNA methylation, histone modifications, or epigenetic regulatory pathways and enzymes may be involved in the development of many neurodegenerative diseases.
Toxins
Toxic substances, including alcohol or lead, result in neurodegeneration, especially with long-term exposure. Toxins might directly induce neuronal cell death or impair neuronal or glial cell function leading to neurodegeneration.
Protein Misfolding and Impaired Protein Clearance
A subclass of neurodegenerative diseases, termed proteinopathies, are associated with protein misfolding and formation of aggregates, often in the form of Lewy bodies, neurofibrillary tangles, or plaques characteristic of the respective disease. Accumulation of proteins and aggregate formation leading to protein toxicity is thought to be one of the fundamental mechanisms driving pathology in these neurodegenerative diseases. Protein aggregation may be caused by protein variants more prone to aggregate formation, impairments in ubiquitin-proteasome, autophagolysosome protein clearance, or – in case of prion diseases – a transmissible form of misfolded protein able to induce misfolding in normal variants of the same protein.
Altered Cell Signaling
Abnormal cell signaling, such as disrupted pre-synaptic input or impaired intracellular signaling pathways, can contribute to the pathogenesis of neurodegenerative diseases, especially as neuronal vitality and survival often depend on synaptic activity and extrinsic survival signals.
Impaired Energy Metabolism
Neurons are highly metabolically active cells: neuronal signal transduction directs high levels of protein synthesis and high energy demands, with myriads of transmembrane transporters and pumps requiring ATP supply. Neurons are therefore very susceptible to minor disruptions in their energy metabolism. They heavily rely on the optimal supply of oxygen, glucose, and lactate by the bloodstream and astrocytic glia. Disruption of mitochondrial function quickly results in catastrophic effects, causing oxidative stress or apoptotic cell death.
Oxidative Stress
The high density of mitochondria and their high activity levels in most neurons results in large amounts of reactive oxygen species (ROS) being produced. Mediation of oxidative stress by antioxidants is vital for neurons. Impaired superoxide dismutase or glutathione peroxidase correlates with many neurodegenerative diseases. Additionally, oxidative stress might stem from inflammation or altered glial function and lead to neurodegeneration.
DNA Damage
Accumulation of DNA damage combined with a decline in the effectiveness of the DNA repair machinery has been linked to dementia and cognitive decline in general, as well as to various neurodegenerative diseases.
Impaired Cytoskeleton and Axonal Transport
Neurons are physically large cells, with a large portion of the cytoplasm located at a significant distance from the perinuclear cytoplasm with all its metabolic machinery. Cellular function and wellbeing strongly depend on a distribution mechanism along the axon, termed axonal transport. Metabolites, such as proteins and lipids, and vesicles and organelles, are transported along the axon in both directions. This transport may be passive, but more often, it relies on linker proteins and active carriers that pull the cargo along the axonal cytoskeleton. Disruptions of the transport mechanism or the cytoskeletal scaffold it relies on can have catastrophic effects on neuronal function.
Neuroinflammation
Inflammation in nervous tissue can occur due to trauma, infection, stroke, toxic metabolites, or autoimmunity. Inflammatory processes can reduce available metabolites, increase oxidative stress, disruption of cell-to-cell contacts and tissue architecture, synaptic pruning, disruption, and phagocytosis of cellular extensions, such as myelin, and even directly induce apoptotic cell death in glia and neurons. Acute inflammation severely disrupts neural function, even if it is often reversible. Repeated or chronic inflammation will typically result in progressive neurodegeneration.
Demyelination
Loss of the nerve-insulation myelin sheaths due to injury, toxins, metabolic alterations, or inflammation leaves the axon exposed to detrimental environmental influences and leads to short-term disruption of neuronal function and the loss of rapid, salutatory signal transduction. Demyelination results in significantly increased energy demands and altered cellular signaling. Prolonged demyelination will directly result in neurodegeneration.
Glial Dysfunction
Neurons rely on glial support in various aspects. Glial cells, such as astrocytes and oligodendrocytes (or Schwann cells in case of the PNS), provide neurons and axons with vitally essential cellular signals and metabolic support. Glia even disposes of neuronal cellular waste, such as toxic metabolites and ROS. Loss of glia or glial cell function and acquired glial senescence can result in accelerated neurodegeneration or cause it entirely.
Induced Cell Death
The triggering of induced cell death, especially apoptosis, is one of the main factors leading to neuronal loss in neurodegenerative diseases. Cell death might be triggered extrinsically, most commonly during inflammation events by immune cells. Still, it might also be triggered by extreme impairments of mitochondria, overloaded autophagy pathways, or structural damage to the cell due to protein aggregates.
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Figure 1. Common factors causing or benefitting neurodegeneration
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The Most Common Neurodegenerative Diseases
Hundreds of neurodegenerative diseases are described, but a few of the most common neurodegenerative diseases, particularly some proteinopathies, have the highest prevalence and impact. The majority of them are age-related neurodegenerative disorders, and their prevalence is expected to further increase with an aging human population.
Alzheimer’s disease (AD)
The pathology of AD is primarily characterized by the occurrence of senile plaques and neurofibrillary tangles. These aggregates consist of small beta-amyloid peptides, which are cleaved from amyloid precursor protein and self-assemble into dense extracellular deposits, resulting in neurodegeneration and neuroinflammation. AD leads to gross atrophy of the cerebral cortex and some subcortical structures and is with 60-70% of the cases the most frequent cause of dementia.
Parkinson’s disease (PD)
PD is the second most common neurodegenerative disorder and typically manifests mainly through motoric defects, such as bradykinesia and tremor. Typical for PD is the formation of alpha-synuclein-ubiquitin protein complexes and aggregates in Lewy bodies in neurons of the substantia nigra and subsequent loss of the motor neurons in this brain area. How exactly protein accumulation and cell death are connected remains speculative.
Amyotrophic Lateral Sclerosis (ALS)
ALS is characterized by the degeneration of upper and lower motor neurons, resulting in progressive skeletal muscle weakness and gradual loss of voluntary movement. The exact cause of ALS remains unknown, but more than 20 genes have been associated with the disease. The pathological hallmark of ALS is the inclusion bodies of abnormally aggregated protein in the cytoplasm of motor neurons. Research has further linked ALS with astrocytes exhibiting cytotoxic effects on neurons.
Huntington’s disease (HD)
In contrast to the neurodegenerative diseases with spontaneous onset summarized above, HD is a genetic disease inherited in an autosomal dominant fashion. Mutations in the huntingtin gene lead to abnormal aggregation of huntingtin in inclusion bodies within neurons. These aggregates are thought to be directly neurotoxic as well as impair axonal transport. Despite the genetic origin, the pathology typically manifests itself late in life, suggesting a cumulative neurotoxic effect. The striatal and cortical neurons are primarily affected, leading to a lack of mental abilities, coordination, and motor skills.
Multiple Sclerosis (MS)
An autoimmune reaction against myelin causes MS. The body’s immune system attacks components of CNS myelin, resulting in demyelination, local inflammation, and ultimately neuronal damage. Due to the inflammatory nature of the disease, it typically manifests itself initially in relapsing-remitting cycles of symptoms, where acute inflammation impairs nervous system function. Once the inflammation has receded, repair and compensation mechanisms can initially ease or eliminate symptoms until the underlying neuronal damage becomes increasingly evident, and patients typically show a progressive decline. The clinical appearance of MS can be highly variable, depending on the location and intensity of inflammatory foci.
Neuroscience at Enzo
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