This suggests that defective axons are not only present in diseased neurons, but also that they may cause certain pathological insult due to accumulation of organelles. Axonal transport can be disrupted by a variety of mechanisms including damage to: kinesin and cytoplasmic dynein, microtubules, cargoes, and mitochondria. When axonal transport is severely disrupted a degenerative pathway known as Wallerian-like degeneration is often triggered. Programmed cell death
Programmed cell death (PCD) is death of a cell in any form, mediated by an intracellular program. This process can be activated in neurodegenerative diseases including Parkinsons disease, amytrophic lateral sclerosis, Alzheimers disease and Huntingtons disease. PCD observed in neurodegenerative diseases may be directly pathogenic; alternatively, PCD may occur in response to other injury or disease processes. Apoptosis (type I)
Apoptosis is a form of programmed cell death in multicellular organisms. It is one of the main types of programmed cell death (PCD) and involves a series of biochemical events leading to a characteristic cell morphology and death. Extrinsic apoptotic pathways: Occur when factors outside the cell activate cell surface death receptors (e.g., Fas) that result in the activation of caspases-8 or -10. Intrinsic apoptotic pathways: Result from mitochondrial release of cytochrome c or endoplasmic reticulum malfunctions, each leading to the activation of caspase-9. The nucleus and Golgi apparatus are other organelles that have damage sensors, which can lead the cells down apoptotic pathways.Caspases (cysteine-aspartic acid proteases) cleave at very specific amino acid residues. There are two types of caspases: initiators and effectors. Initiator caspases cleave inactive forms of effector caspases.
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.