In Huntingtons 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 (Alzheimers disease, Parkinsons disease, and Huntingtons 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
The process of neurodegeneration is not well understood, so the diseases that stem from it have, as yet, no cures. Animal models in research
In the search for effective treatments (as opposed to palliative care), investigators employ animal models of disease to test potential therapeutic agents. Model organisms provide an inexpensive and relatively quick means to perform two main functions: target identification and target validation. Together, these help show the value of any specific therapeutic strategies and drugs when attempting to ameliorate disease severity. An example is the drug Dimebon by Medivation, Inc. In 2009 this drug was in phase III clinical trials for use in Alzheimers disease, and also phase II clinical trials for use in Huntingtons disease.
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 Alzheimers, Parkinsons, Huntingtons, 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 cells 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. Increased oxidative DNA damage in the brain is associated with Alzheimers disease and Parkinsons disease. Defective DNA repair has been linked to neurodegenerative disorders such as Alzheimers disease, amyotrophic lateral sclerosis, ataxia telangiectasia, Cockayne syndrome, Parkinsons disease and xeroderma pigmentosum. Axonal transport
Axonal swelling, and axonal spheroids have been observed in many different neurodegenerative diseases.