Mitochondria and Neurodegenerative Diseases
Oxidative stress is considered to be a key contributor to the onset and progression of many neurological disorders. Oxidative stress results when the production of reactive oxygen species (ROS) exceeds their elimination by antioxidant pathways. The brain, with its high metabolic rate and oxygen consumption, is particularly susceptible to oxidative stress. The brain also has limited antioxidant defense mechanisms compared to other tissues. Cumulative oxidative damage, over time, may explain the late life onset and slowly progressive nature of many neurodegenerative diseases.
Mitochondrial DNA (mtDNA) in the brain is especially vulnerable to oxidative damage as a result of the proximity of mtDNA to the respiratory chains, which are the primary cellular generators of ROS. Under physiologic conditions, mtDNA damage and repair are balanced, but if mtDNA repair is defective or oxidative damage exceeds the repair capacity, damage becomes permanent and leads to impairment of cellular metabolism. Since neurons are post-mitotic and do not replicate, there is limited capacity for regeneration in the adult nervous system. A significant amount of mtDNA damage can lead to selective loss of damaged neurons
and be a key factor in aging and neurodegeneration. The brain, therefore, requires significant DNA repair activity to prevent the type of damage that leads to neurodegenerative disease. The most common oxidative mtDNA lesion is 8-oxoguanine (8-oxoG), and one of the key BER enzymes responsible for repair of oxidized mtDNA is 8-oxoguanine DNA glycosylase (OGG1). Among various tissues, the expression of OGG1 gene is found to be the highest in the brain.
Learn more about mitochondrial damage and neuroinflammation
Alzheimer’s disease (AD) is the most common form of dementia in adults, especially in people aged 65 years or over. AD is currently estimated to affect over 44 million people worldwide, with this number expected to double every 20 years.
Learn more about Alzheimer's disease.
Parkinson’s disease (PD), with a prevalence of 2% of the population over the age of 65, is one of the most common neurodegenerative disorders and is characterized by resting tremor, rigidity, and bradykinesia.
Learn more about Parkinson's disease.
Amyotrophic Lateral Sclerosis
Amyotrophic lateral sclerosis (ALS), also known as Lou Gehrig’s disease, the most common adult-onset neurodegenerative disease, is an age-related neurological disease caused by the progressive death of motor neurons, the nerve cells that directly signal muscles to contract or relax.
Learn more about ALS.
Multiple sclerosis (MS), an autoimmune disease of the central nervous system (CNS), is the most common, non-traumatic disabling disease affecting those in early adulthood. Within 15 years after onset of the disease, fifty percent of patients need help walking. Worldwide, an estimated 2.5 million people are affected by MS.
Learn more about MS.
J Clin Invest DOI: 10.1172/JCI45691