About Neurodegenerative Diseases
What are Neurodegenerative diseases?
Neurodegenerative diseases are characterised by progressive dysfunction and loss of synapses (a site of transmission of electrical or chemical signal between nerve cells or other effector cells), neuron (the basic working units of the brain) and their networks. This is associated with a response from the supporting tissue called glia (astroglia, oligodendroglia, microglia).
A crucial component of neurodegenerative diseases is the deposition of physicochemically altered variants of physiological proteins predominantly in the nervous system. Importantly, not only neurons but glial cells also accumulate these pathological proteins.
The following proteins are associated with the majority of sporadic and genetic adult-onset neurodegenerative diseases:
Amyloid-beta (Aβ), which is cleaved from the transmembrane amyloid precursor protein (APP), encoded by a gene on chromosome 21q21.3;
α-synuclein, a 140-aa protein encoded by a gene (SNCA) on chromosome 4;
Prion protein (PrP), which is a 253-aa protein encoded by the gene of PrP (PRNP) located on chromosome 20;
The microtubule-associated protein tau is represented by different isoforms and encoded by a single gene (MAPT) on chromosome 17q21;
Transactive response DNA-binding protein 43 (TDP-43), a highly conserved nuclear 414-aa protein encoded by the TARDBP gene on chromosome 1;
FET (abbreviation of the following three proteins) proteins, which include the fused in sarcoma (FUS; its gene on chromosome 16), Ewing’s sarcoma RNA-binding protein 1 (EWSR1) and TATA-binding protein-associated factor 15 (TAF15).
Further proteins are associated with hereditary disorders such as neurological trinucleotide repeat disorders, ferritin-, neuroserpin-related conditions, and familial cerebral amyloidosis.
Neurodegenerative diseases are also called proteinopathies.
What are the symptoms of neurodegenerative disease?
Cognitive decline, dementia and alterations in high-order brain functions;
Movement disorders, including parkinsonism or uncontrollable movements or progressive muscular weakness;
Combinations of these.
How common are neurodegenerative diseases?
Neurodegenerative diseases are very common especially with ageing. The most common forms are Alzheimer’s disease (up to 1000 individuals affected in 100,000 depending on the age group) and Parkinson’s disease (around 20 individuals affected in 100,000 a year but there are several other conditions that are less known in the public and are less frequent (around 1-10 individuals affected in 100,000 a year). Some examples of these are progressive supranuclear palsy (PSP; TAU proteinopathy), corticobasal degeneration (CBD; TAU proteinopathy), multiple system atrophy (MSA; SYNUCLEIN proteinopathy), amyotrophic lateral sclerosis (ALS) called also as motor neuron disease (MND; Lou Gherig’s disease; TDP-43 proteinopathy), different forms of frontotemporal lobar degenerations associated with frontotemporal dementias (TAU, TDP-43, FET proteinopathies). Prion proteinopathies (for example Creutzfeldt-Jakob disease) are very rare and affect 2-3 individuals/1 million/year.
Classification
The classification of neurodegenerative diseases is based on the clinical presentation, brain areas involved, cell types affected, altered proteins, and aetiology if known (for example gene alterations or if an acquired pathway is recognized, for example, in prion diseases). See for example.
Basic mechanisms
Major pathways can be summarized as follows:
oxidative stress, formation of free radicals/reactive oxygen species, mitochondrial dysfunction, impaired bioenergetics and DNA damage, neuroinflammatory processes and disruption of cellular/axonal transport
proteins capable of misfolding associated with altered conformation (3D structure)
involvement of protein processing systems, unfolded protein response, and protein elimination pathways, such as the ubiquitin-proteasome system and the autophagy-lysosome pathway
cell-to cell propagation of proteins (called also as prion-like spreading) and recognition of sequential involvement of anatomical regions, leading to the development of stages and phases of pathological protein deposits