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. Only about 5-10% of cases of ALS are due to a family history of ALS (fALS), with the remaining 90-95% being considered sporadic (sALS).  A few risk factors for ALS have been identified to date and these include increasing age, family history, and gender. The onset of ALS typically begins at the age of 50 years old for genetically inherited cases and at the age of 60 years old for sporadic cases, although the disease can start at any age. Every year, two to three people out of 100,000 are estimated to be affected by ALS in the United States and Europe.


There is presently no effective treatment for the disease with most patients surviving only 2 to 5 years after the onset of symptoms, though survival times can range from a few months to several decades. Patients with ALS develop progressive weakness, muscle atrophy, and eventual paralysis. Drugs currently approved by the FDA for the treatment of ALS add only 2 to 3 months to life expectancy. Though the molecular events that underlie the death of motor neurons are not fully known, accumulating evidence suggests that oxidative stress and increased inflammatory responses along with dysfunction of glial cells (supportive cells in the central nervous system), are critical factors in the development of ALS. Oxidative stress, in particular, is considered a central component in the progression of ALS.


Markers of oxidative damage have been detected in the spinal cords of both sALS and fALS patients.  Many clinical studies have analyzed oxidative stress markers in ALS and demonstrated that levels of prooxidative stress markers, malondialdehyde (MDA) and 8-oxoG were increased in the peripheral blood, urine and cerebrospinal fluid of ALS patients. DNA damage, due to oxidative stress, accumulates in the neurons over time, especially in mitochondrial DNA (mtDNA), and plays a central role in the development of several neurodegenerative diseases, including ALS.


Studies suggest that the S326C variant of OGG1 could be a susceptibility factor for sALS. The targeting of OGG1 to increase its activity in such subjects, hence, could provide a means to offset the loss of oxidative DNA damage capacity.