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.
It is thought that defects in protein transport machinery and regulation, such as RAB1, may play a role in this disease mechanism. Impaired axonal transport of alpha-synuclein may also lead to its accumulation in Lewy bodies. Experiments have revealed reduced transport rates of both wild-type and two familial Parkinsons disease-associated mutant alpha-synucleins through axons of cultured neurons. Membrane damage by alpha-synuclein could be another Parkinsons disease mechanism.The main known risk factor is age. Mutations in genes such as α-synuclein (SNCA), leucine-rich repeat kinase 2 (LRRK2), glucocerebrosidase (GBA), and tau protein (MAPT) can also cause hereditary PD or increase PD risk. While PD is the second most common neurodegenerative disorder, problems with diagnoses still persist. Problems with the sense of smell is a widespread symptom of Parkinsons disease (PD), however, some neurologists question its efficacy. This assessment method is a source of controversy among medical professionals. The gut microbiome might play a role in the diagnosis of PD, and research suggests various ways that could revolutionize the future of PD treatment. Huntingtons disease
Huntingtons disease (HD) is a rare autosomal dominant neurodegenerative disorder caused by mutations in the huntingtin gene (HTT). HD is characterized by loss of medium spiny neurons and astrogliosis. The first brain region to be substantially affected is the striatum, followed by degeneration of the frontal and temporal cortices. The striatums subthalamic nuclei send control signals to the globus pallidus, which initiates and modulates motion.