Extensive research has been done using the models of nematode (C. elegans), and fruit fly (Drosophila), mice, and non-human primates.Nine inherited neurodegenerative diseases are caused by the expansion of the CAG trinucleotide and polyQ tract, including Huntingtons disease and the spinocerebellar ataxias. Epigenetics
The presence of epigenetic modifications for certain genes has been demonstrated in this type of pathology. An example is FKBP5 gene, which progressively increases its expression with age and has been related to Braak staging and increased tau pathology both in vitro and in mouse models of AD. Protein misfolding
Several neurodegenerative diseases are classified as proteopathies as they are associated with the aggregation of misfolded proteins. Protein toxicity is one of the key mechanisms of many neurodegenrative diseases. alpha-synuclein: can aggregate to form insoluble fibrils in pathological conditions characterized by Lewy bodies, such as Parkinsons disease, dementia with Lewy bodies, and multiple system atrophy. Alpha-synuclein is the primary structural component of Lewy body fibrils. In addition, an alpha-synuclein fragment, known as the non-Abeta component (NAC), is found in amyloid plaques in Alzheimers disease. tau: hyperphosphorylated tau protein is the main component of neurofibrillary tangles in Alzheimers disease; tau fibrils are the main component of Pick bodies found in behavioral variant frontotemporal dementia. amyloid beta: the major component of amyloid plaques in Alzheimers disease. prion: main component of prion diseases and transmissible spongiform encephalopathy. Intracellular mechanisms
Protein degradation pathways
Parkinsons disease and Huntingtons disease are both late-onset and associated with the accumulation of intracellular toxic proteins.
This activates the effectors that in turn cleave other proteins resulting in apoptotic initiation. Autophagic (type II)
Autophagy is a form of intracellular phagocytosis in which a cell actively consumes damaged organelles or misfolded proteins by encapsulating them into an autophagosome, which fuses with a lysosome to destroy the contents of the autophagosome. Because many neurodegenerative diseases show unusual protein aggregates, it is hypothesized that defects in autophagy could be a common mechanism of neurodegeneration. Cytoplasmic (type III)
PCD can also occur via non-apoptotic processes, also known as Type III or cytoplasmic cell death. For example, type III PCD might be caused by trophotoxicity, or hyperactivation of trophic factor receptors. Cytotoxins that induce PCD can cause necrosis at low concentrations, or aponecrosis (combination of apoptosis and necrosis) at higher concentrations. It is still unclear exactly what combination of apoptosis, non-apoptosis, and necrosis causes different kinds of aponecrosis. Transglutaminase
Transglutaminases are human enzymes ubiquitously present in the human body and in the brain in particular.The main function of transglutaminases is bind proteins and peptides intra- and intermolecularly, by a type of covalent bonds termed isopeptide bonds, in a reaction termed transamidation or crosslinking.Transglutaminase binding of these proteins and peptides make them clump together. The resulting structures are turned extremely resistant to chemical and mechanical disruption.Most relevant human neurodegenerative diseases share the property of having abnormal structures made up of proteins and peptides.Each of these neurodegenerative diseases have one (or several) specific main protein or peptide. In Alzheimers disease, these are amyloid-beta and tau. In Parkinsons disease, it is alpha-synuclein.