Genetics Many neurodegenerative diseases are caused by
genetic mutations, most of which are located in completely unrelated genes. In many of the different diseases, the mutated gene has a common feature: a repeat of the CAG nucleotide triplet. CAG codes for the amino acid
glutamine. A repeat of CAG results in a
polyglutamine (polyQ) tract. Diseases associated with such mutations are known as
trinucleotide repeat disorders. Polyglutamine repeats typically cause dominant pathogenesis. Extra glutamine residues can acquire toxic properties through a variety of ways, including irregular protein folding and degradation pathways, altered subcellular localization, and abnormal interactions with other cellular proteins. Nine inherited neurodegenerative diseases are caused by the expansion of the CAG trinucleotide and polyQ tract, including
Huntington's 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 Parkinson's 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
Alzheimer's disease. •
tau: hyperphosphorylated tau protein is the main component of
neurofibrillary tangles in Alzheimer's 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 Alzheimer's disease. •
prion: main component of
prion diseases and
transmissible spongiform encephalopathy.
Intracellular mechanisms Protein degradation pathways Parkinson's disease and Huntington's disease are both late-onset and associated with the accumulation of intracellular toxic proteins. Diseases caused by the aggregation of proteins are known as
proteopathies, and they are primarily caused by aggregates in the following structures: and cause extensive tubulation and vesiculation when incubated with artificial phospholipid vesicles. The tubes formed from these lipid vesicles consist of both micellar as well as bilayer tubes. Extensive induction of membrane curvature is deleterious to the cell and would eventually lead to cell death. Apart from tubular structures, alpha-synuclein can also form lipoprotein nanoparticles similar to apolipoproteins.
Mitochondrial dysfunction The most common form of cell death in neurodegeneration is through the intrinsic mitochondrial apoptotic pathway. This pathway controls the activation of caspase-9 by regulating the release of
cytochrome c from the
mitochondrial intermembrane space.
Reactive oxygen species (ROS) are normal byproducts of mitochondrial respiratory chain activity. ROS concentration is mediated by mitochondrial antioxidants such as manganese superoxide dismutase (SOD2) and
glutathione peroxidase. Over production of ROS (
oxidative stress) is a central feature of all neurodegenerative disorders. In addition to the generation of ROS, mitochondria are also involved with life-sustaining functions including calcium homeostasis, PCD,
mitochondrial fission and
fusion, lipid concentration of the mitochondrial membranes, and the mitochondrial permeability transition.
Mitochondrial disease leading to neurodegeneration is likely, at least on some level, to involve all of these functions. There is strong evidence that mitochondrial dysfunction and oxidative stress play a causal role in neurodegenerative disease pathogenesis, including in four of the more well known diseases
Alzheimer's,
Parkinson's,
Huntington's, and
amyotrophic lateral sclerosis.
Neurons are particularly vulnerable to
oxidative damage due to their strong metabolic activity associated with high
transcription levels, high oxygen consumption, and weak
antioxidant defense.
DNA damage The brain metabolizes as much as a fifth of consumed oxygen, and
reactive oxygen species produced by oxidative metabolism are a major source of
DNA damage in the
brain. Damage to a cell's
DNA is particularly harmful because DNA is the blueprint for protein production and unlike other molecules it cannot simply be replaced by re-synthesis. The vulnerability of post-mitotic neurons to DNA damage (such as oxidative lesions or certain types of DNA strand breaks), coupled with a gradual decline in the activities of
repair mechanisms, could lead to accumulation of DNA damage with age and contribute to brain aging and neurodegeneration. DNA single-strand breaks are common and are associated with the neurodegenerative disease ataxia-
oculomotor apraxia. 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 Parkinson's disease, amytrophic lateral sclerosis, Alzheimer's disease and Huntington's disease. PCD observed in neurodegenerative diseases may be directly pathogenic; alternatively, PCD may occur in response to other injury or disease processes.
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. This activates the effectors that in turn cleave other proteins resulting in apoptotic initiation. 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
Alzheimer's disease, these are
amyloid-beta and
tau. In
Parkinson's disease, it is
alpha-synuclein. In
Huntington's disease, it is
huntingtin.
Transglutaminase substrates: Amyloid-beta,
tau,
alpha-synuclein and
huntingtin have been proved to be
substrates of
transglutaminases in vitro or in vivo, that is, they can be
bonded by trasglutaminases by
covalent bonds to each other and potentially to any other transglutaminase substrate in the brain.
Transglutaminase augmented expression: It has been proved that in these neurodegenerative diseases (Alzheimer's disease, Parkinson's disease, and Huntington's disease) the
expression of the
transglutaminase enzyme is increased.
Presence of isopeptide bonds in these structures: The presence of
isopeptide bonds (the result of the
transglutaminase reaction) have been detected in the
abnormal structures that are characteristic of these neurodegenerative diseases.
Co-localization: Co-localization of transglutaminase mediated
isopeptide bonds with these
abnormal structures has been detected in the autopsy of brains of patients with these diseases. ==Management==