Amyotrophic Lateral Sclerosis (Lou Gehrig’s Disease)
Possible Causes of ALS
Because SOD1 gene mutations can cause familial ALS, many researchers have studied this protein to determine how it plays a role in the death of motor neurons. SOD1 is a gene that codes for superoxide dismutase (SOD), an enzyme which helps convert superoxide radicals into less harmful molecules. Superoxide molecules are a form of free radical or reactive oxygen species, a class of molecules that can damage the DNA, proteins, and membranes of cells causing them to die (Rothstein 2009). If SOD is either functioning poorly or is present in inadequate quantities, rampant oxidative stress driven by unabated superoxide molecules can damage tissue and contribute to disease.
Approximately 20% of familial cases and 2% of all ALS cases are linked to SOD1 gene mutations (Sung 2002; Andersen 2006; Chiò 2008). This suggests that the accumulation of superoxide molecules and other free radicals could contribute to ALS. In addition to increasing superoxide levels, SOD1 mutations can damage neurons in other ways. For example, mutant SOD1 produces abnormal SOD molecules which are theorized to serve as the seed for large clusters of misfolded proteins that are toxic to neurons (Karch 2009; Lindberg 2002).
Studies have found elevated levels of oxidative stress within the central nervous system as well as peripherally in ALS (Miana-Mena 2011; Hensley 2006; Ilieva 2007; Kanekura 2009). This suggests that motor neuron death in ALS is related to increased levels of reactive oxygen species. These conditions contribute to the neuronal death and muscle wasting common in ALS. Oxidative stress can be relieved by increasing the concentration of antioxidants such as beta-carotene (Dawson 2000), vitamins C (Mandl 2009) and E (Colombo 2010), as well as the mineral selenium (Sanmartin 2011). Many other supplements, such as coenzyme Q10, also have antioxidant properties.
Glutamate is an important neurotransmitter. Under normal conditions, its concentrations are tightly regulated. However, it appears the system regulating glutamate concentration in patients with ALS may be disturbed (Rothstein 1995b), resulting in an accumulation of glutamate in the space (synapse) between cells (Cameron 2002). This excess glutamate may excite nerve cells beyond their capacity resulting in nerve cell death. Patients with ALS have elevated levels of glutamate in their cerebrospinal fluid, support this hypothesis (Rothstein 1990, Shaw 1995). Mutant glutamate transport proteins are also associated with sporadic forms of ALS, further supporting the idea that elevated levels of glutamate-mediated excitation can kill motor neurons in ALS patients (Lin 1998; Rothstein 1995; Dunlop 2003). Some of the most powerful evidence supporting the critical role that glutamate plays in the pathology of ALS is the effectiveness of the medication riluzole, which inhibits glutamate’s effects on the nervous system. It modulates the release of glutamate, thereby improving survival for ALS patients. Its effect however is modest, suggesting that excess glutamate is not the sole cause of the disease.
The mitochondria provide energy for all cells, including neurons. Unfortunately, mitochondria also produce reactive oxygen species as a byproduct of energy generation. Mitochondrial dysfunction can result in the production of excessive amounts of superoxide, causing extensive cell damage and death. Accumulation of superoxide is prevented by SOD and other enzymes (Brand 2011).
There are a number of ways in which the mitochondria in motor neurons may become impaired in ALS (Shi 2010). In animal models of ALS, dysfunction of mitochondria in motor neurons occurs before any other observable pathologic changes, suggesting this is an early event in the progression of the disease (Kong 1998). Mutant forms of SOD appear to lead to mitochondrial dysfunction (Liu 2004). Studies of both human and animal neurons have found extensive mitochondrial dysfunction associated with ALS (Cassarino 1999; Beal 2005; Martin 2011; Cozzolino 2011; Kawamata 2011; Faes 2011). In addition, some patients with ALS appear to have impaired mitochondrial function in their muscle fibers (Crugnola 2010).
Animal models of ALS show abnormal transport of mitochondria in their motor neurons which could further contribute to the progression of the disease (De Vos 2007). Additionally, because proper mitochondrial function is so essential, other yet unidentified processes could be altered when mitochondrial health is impaired (Fosslien 2001). Along these lines, an emerging theory linking excitotoxicity and mitochondrial dysfunction suggests that an accumulation of lactate, a metabolic byproduct which is toxic (especially to nerve cells) at high concentrations may play a role in ALS progression (Vadakkadath Meethal 2012). This theory (a.k.a. the lactate dyscrasia theory) proposes that mitochondrial dysfunction partly contributes to an accumulation of lactate in the junction of motor neurons and muscle cells (the neuromuscular junction (NMJ)) leading to death of both the nerve and muscle cells, thereby requiring the remaining muscle cells to work harder-than-normal to generate the force necessary for motor control. However, since lactate is a metabolic byproduct and greater metabolic demand increases lactate production, the remaining muscle cells produce even more lactate than usual due to their increased workload, hastening the accumulation of lactate and exacerbating neuronal destruction and muscular atrophy. This theory also proposes that malfunction of an as yet undiscovered lactate shuttle within the NMJ may be a pathological feature of ALS, suggesting that supporting mitochondrial function may optimize lactate metabolism and combat the toxicity caused by accumulation of excess lactate. If this theory is correct, then combining drugs that inhibit lactate accumulation such as nizofenone (Matsumoto 1994) with nutrients that support mitochondrial function (like coenzyme Q10 and pyrroloquinoline quinone (PQQ) might be an effective therapy for ALS.
Heavy metals and environmental agents. The role of heavy metals in ALS is highly controversial. Since clusters of ALS patients have been found in certain geographical areas, researchers have searched for an underlying environmental theme such as heavy metal poisoning. For example, researchers have found that elevated levels of lead are associated with a higher risk of ALS (Fang 2010). Another toxin which has been identified as a potential mediator for ALS is mercury, though the link between mercury and ALS risk is not as clear (Callaghan 2011, Mano 1990). These toxins can lead to subtle cellular changes such as interfering with the methylation of DNA (Rooney 2011). Other studies however have failed to show a link between ALS and any of the common heavy metals (Gresham 1986).
Beta-N-methylamino-L-alanine (BMAA), a neurotoxin made by certain bacteria may play an important role in the development of ALS. BMAA may be implicated in the high incidence of ALS in Guam, where these bacteria are commonly found in the seeds of the Cycas circinalis plant (Banack 2010).
Exposure to pesticides may also increase the risk of developing ALS (Johnson 2009). Exposure to pesticides in the grass on the playing field is one theory put forth to explain the unusually high incidence of ALS in Italian soccer players (Chio 2009).
While there is good reason to think that neurotoxic agents like these may be somehow linked to degenerative brain and nerve conditions like ALS, researchers have been unable to meet the demanding scientific standard needed to establish a causal relationship (Caban-Holt 2005, Johnson 2009).