Neurodegenerative Diseases

The term neurodegenerative disease describes a heterogeneous group of disorders that are characterized by the progressive degeneration of the structure and function of the central nervous system (CNS) or peripheral nervous system, leading to loss of brain functions such as memory, movement, and cognition. Because there is no known way to reverse the progressive degeneration of neurons, these diseases are considered to be incurable. The late manifestation of clinical symptoms, usually years or even decades after disease onset, continues to impede therapies to prevent disease progression or regenerate or replace affected neurons.

Neurodegenerative diseases may occur due to age: Alzheimer's disease (AD), Parkinson's disease (PD); or due to genetic mutations which impact nerve system cell function: Huntington's disease, early onset AD or PD, and Amyotrophic Lateral Sclerosis (ALS). Furthermore, neurodegenerative diseases show a variety of pathological overlaps. Here we provide an overview about selected key processes reoccurring in neurodegenerative diseases including proteinopathies, neuroinflammation, mitochondrial dysfunction, errors in RNA and altered cell signaling.

These similarities suggest that therapeutic advances against one neurodegenerative disease might be effective against other diseases as well. Research on this topic is of high relevance especially in the context of an aging world population as aging is an important trigger factor of neuronal diseases. antibodies-online can support your research on neurodegenerative diseases with high quality antibodies and proteins for important neurodegenerative markers and targets.

Proteinopathies

Biomedical research revealed similarities on subcellular level, including atypical protein assemblies like proteinopathy - a single type of proteinopathy can be associated with multiple diseases - and induced cell death. The proteinopathies include such diseases as Alzheimer's disease, Parkinson's disease, Creutzfeldt–Jakob disease and other prion diseases, amyloidosis, multiple system atrophy, and a wide range of other disorders. In most, if not all proteinopathies, a change in the 3-dimensional folding conformation increases the tendency of a specific protein to bind to itself. The misfolding of the protein may result in a loss of its usual function as well as a toxic gain-of-function. In this aggregated form, the protein is resistant to clearance. These deposits of insoluble peptides or proteins accumulate with time, and they become more toxic when neurons are old.

Certain risk factors can promote the self-assembly of a protein and therefore proteinopathy. These include increased expression, destabilizing changes in the primary amino acid sequence of the protein, post-translational modifications, changes in temperature or pH. Advancing age is a strong risk factor - in the aging brain, multiple proteopathies can overlap. The following table gives an overview of different proteinopathies and their link to neurodegenerative diseases.

Protein Components and their Pathology Implication

Neuroinflammation

Microglia, the primary immune cells in the CNS, are activated upon disruption of the physiological homeostasis. Activated microglia destroy pathogens, remove damaged cells, eliminate toxic substances, prevent spread of infections and injury, release neurotrophic factor, and promote tissue repair and regrowth. However, tight coordination among activated microglia, astroglia, and neurons is essential for tissue repair and for fighting off infection of healthy CNS cells. In neurodegenerative diseases beneficial effects of neuroinflammation appear to be reduced and excessive inflammation leads to neuronal loss instead. Reactive microgliosis, the chronical activation of microglia, is a hallmark of several neurodegenerative diseases and is implicated in progression of AD and PD. Driving factors include aggregated α-synuclein and A-β-amyloid or imbalanced neuro-transmitters.

Mitochondrial Dysfunction

Because of their high energy requirements, neurons are especially vulnerable to injury and death from dysfunctional mitochondria. Pathological and physiological evidence reveals mitochondrial dysfunction in all major neurodegenerative diseases. Catalyzed by iron, copper, and trace redox-active metals, metal-mediated oxidative stress plays a key role in mitochondrial dysfunction. Questions remain as to whether mitochondrial dysfunction is causal to neurodegenerative disease. Even if is not causal, mitochondrial dysfunction is still highly important and likely contributory to disease.

Altered Cell Signaling

Cellular communication and signaling are keys to coordinate the functions of the different cell types that constitute organisms. These systems control processes such as inter- and intracellular transport, changes in cell morphology, energy consumption, and accumulation, cell differentiation, cell migration, cell proliferation or cell death. Based on the theory of the neurovascular unit, abnormal cell-cell communication, for example disrupted presynaptic input, as well as disrupted intracellular signaling contribute to the pathogenesis of neurodegenerative disease. The mechanism behind is not yet fully understood, astrocyte dysfunction is thought to play a central role. Understanding the signal transduction pathways that regulate gene expression will help efforts to develop therapeutic interventions.

Errors in RNA

Various neuromuscular and neurodegenerative diseases—including certain types of amyotrophic lateral sclerosis (ALS), frontotemporal dementia, and Alzheimer’s disease—feature toxic RNA or RNA-binding proteins. Non-coding RNAs are diverse classes of RNA molecules that are not translated into proteins. They are disproportionately expressed within the CNS, where they have roles in gene expression, development, neural network plasticity and connectivity, stress response, and brain aging. Antisense oligonucleotides (ASOs) are being tested to treat RNA errors in human neurodegenerative disease. ASOs are designed to hybridize and then to block disease-related RNA sequences.

Marker for important Neuronal Cells