2 Curr Opin Neurol. 2012 Oct;25(5):530-5. Amyotrophic lateral sclerosis.Tremendous progress has been made in the field of ALS based on recent neuropathological and genetic discoveries. Moreover, the role of metabolism and nutrition in the pathogenesis of the disease is debated and may potentially serve as a future therapeutic target.
3 Areas of Investigation Toxic MineralsOxidative DamageDeficient MethylationMitochondrial DysfunctionKetogenic Diet
4 Toxic Minerals Cadmium Excessive Copper Mercury Lead Excessive Manganese
5 Toxic Minerals: Cadmium Neurotoxicology Jun;22(3):Blood levels of toxic and essential metals in motor neuron disease.Toxic and essential metals have been implicated in the pathogenesis of sporadic motor neuron disease (SMND).The plasma cadmium level was significantly raised in SMND cases.20 ALS 20 controls
6 Toxic Minerals: Cadmium J Cell Biochem Jun 1;98(3):Effects of cadmium on structure and enzymatic activity of Cu,Zn-SOD and oxidative status in neural cells.It has been shown that mutations found in the Cu,Zn-SOD cause 20% of the familial ALS due to its low enzyme activity.In addition to the effect of cadmium on Cu,Zn-SOD, cadmium was also shown to induce neural cell apoptosis.Cadmium decreases the content of Zn(2+), changes the conformation of Cu,Zn-SOD protein to decrease its enzyme activity, and causes oxidative stress-induced neural cell apoptosis.
8 Toxic Minerals: Excessive Copper J Neurol Sci Apr 15;303(1-2):95-9. Epub 2011 Feb 2. Patterns of levels of biological metals in CSF differ among neurodegenerative diseases. We measured the levels of some biological metals: copper (Cu), iron (Fe), magnesium (Mg), manganese (Mn), and zinc (Zn) in the cerebrospinal fluid (CSF) in patients with neurodegenerative diseases (52 patients with amyotrophic lateral sclerosis (ALS)), 21 patients with Alzheimer's disease (AD), and 20 patients with Parkinson's disease (PD) These findings suggest that Cu and Zn in particular play important roles in the onset and/or progression of ALS, AD, and PD. Therefore, Cu-chelating agents and modulators of Cu and Zn such as metallothionein (MT) can be new candidates for the treatment of ALS, AD, and PD
9 Toxic Minerals: Copper Antioxid Redox Signal Jul;11(7):A role for copper in the toxicity of zinc-deficient superoxide dismutase to motor neurons in amyotrophic lateral sclerosis.The loss of zinc from SOD1 results in the remaining copper in SOD1 to become extremely toxic to motor neurons in culture.
10 Oxidative Damage: Melatonin Neurotox Res Jun 28. Melatonin Antioxidative Defense: Therapeutical Implications for Aging and Neurodegenerative Processes. Melatonin also enhances the antioxidant potential of the cell by stimulating the synthesis of antioxidant enzymes including superoxide dismutase. Melatonin preserves mitochondrial homeostasis, reduces free radical generation and protects mitochondrial ATP synthesis The efficacy of melatonin in preventing oxidative damage in either cultured neuronal cells or in the brains of animals treated with various neurotoxic agents, suggests that melatonin has a potential therapeutic value as a neuroprotective drug in treatment of Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), Huntington's disease (HD), stroke, and brain trauma. Therapeutic trials with melatonin indicate that it has a potential therapeutic value as a neuroprotective drug in treatment of AD, ALS, and HD
11 Oxidative Damage: Melatonin J Pineal Res Nov;41(4):Reduced oxidative damage in ALS by high-dose enteral melatonin treatment.Amyotrophic lateral sclerosis (ALS) is the collective term for a motoneuron disease of different etiologies, with oxidative stress as a common molecular denominator of disease progression.We found that melatonin attenuates glutamate-induced cell death of cultured motoneurons.In SOD1(G93A)-transgenic mice, high-dose oral melatonin delayed disease progression and extended survival.In a clinical safety study, chronic high-dose (300 mg/day) rectal melatonin was well tolerated during an observation period of up to 2 yr. Importantly, circulating serum protein carbonyls, which provide a surrogate marker for oxidative stress, were elevated in ALS patients, but were normalized to control values by melatonin treatment. This combination of preclinical effectiveness and proven safety in humans suggests that high-dose melatonin is suitable for clinical trials aimed at neuroprotection through antioxidation in ALS.
12 MelatoninJ Pineal Res Jun 13. doi: /j X x.Overexpression of melatonin membrane receptors increases calcium-binding proteins and protects VSC4.1 motoneurons from glutamate toxicity through multiple mechanisms.Melatonin has shown particular promise as a neuroprotective agent to prevent motoneuron death in animal models of both amyotrophic lateral sclerosis (ALS) and spinal cord injuries (SCI)..Taken together, our findings suggest that the neuroprotection against glutamate toxicity exhibited by melatonin may depend on MT1 and MT2 but not GPR50.
14 MethylationDement Geriatr Cogn Disord Jul;29(6): Epub 2010 Jul 3. Elevated levels of methylmalonate and homocysteine in Parkinson's disease, progressive supranuclear palsy and amyotrophic lateral sclerosis. We found significantly elevated concentrations of Hcy (PD 15.1, PSP 15.8, ALS 13.9, control 11.2 micromol/l) and MMA (PD 3.7, PSP 3.1, ALS 3.7, control 1.8 mg/g) in all patient groups in comparison with controls. Our findings might imply that Hcy and MMA are released as a consequence of neurodegeneration regardless of the underlying cause and serve as surrogate markers of neurodegeneration. Alternatively they might be directly implicated in the pathogenesis of these diseases. Since elevated levels of both Hcy and MMA are neurotoxic, further studies might investigate the effect of vitamin therapy on disease progression.
15 MethylationJ Neurol Sci Jun 15;293(1-2): Decreased level of 5-methyltetrahydrofolate: a potential biomarker for pre-symptomatic amyotrophic lateral sclerosis. Several studies have reported that homocysteine (Hcy) is associated with amyotrophic lateral sclerosis (ALS) Folic acid is decreased at the middle to late stages of the disease. Furthermore, we found that the level of Hcy is markedly elevated after the motor symptoms appeared in the ALS mice. Our study suggests that decreased 5-MTHF level may be a potential biomarker for the early stage of the disease in the ALS mice, which may warrant further validating study of 5-MTHF level in ALS patients.
16 MethylationGenet Test Mol Biomarkers Jul;16(7): Gender-specific association of methylenetetrahydrofolate reductase gene polymorphisms with sporadic amyotrophic lateral sclerosis. Studies have revealed that elevated homocysteine levels can cause damage to motor neurons through multiple neurotoxic mechanisms, thus leading to the pathogenesis of amyotrophic lateral sclerosis (ALS). One way by which homocysteine levels are increased in the body is the consequence of methylenetetrahydrofolate reductase (MTHFR) gene polymorphisms. In conclusion, the evidence we provide here clearly shows that MTHFR C677T and A1298C polymorphisms are genetic risk factors for SALS in women in a gender-specific manner whether they are of spinal or bulbar onset.
17 Methylation Toxicol Appl Pharmacol. 2011 Mar 15;251(3):217-25. Methyl Vitamin B12 but not methylfolate rescues a motor neuron- like cell line from homocysteine-mediated cell death.Homocysteine is an excitatory amino acid implicated in multiple diseases including amyotrophic lateral sclerosis (ALS).We conclude that MeCbl is effective against homocysteine-induced cell death in motor neurons in a ROS-independent manner, via a reduction in caspase activation and apoptosis. MeCbl decreases Hcy induced motor neuron death in vitro in a hybrid cell line derived from motor neuron-neuroblastoma and may play a role in the treatment of late stage ALS where HCy levels are increased in animal models of ALS.
18 Mitochondrial Dysfunction Int J Neurosci Apr;115(4):Lactate stress testing in sporadic amyotrophic lateral sclerosis.Mitochondrial dysfunction is frequently observed in ALS. Mitochondrial dysfunction may result in increased serum lactateThe LST suggests mitochondrial dysfunction in half of the ALS patients. Mitochondrial dysfunction in ALS is related to the clinical severity of the disease
19 Mitochondrial Dysfunction Brain Res Jan 27;1070(1): L-carnitine suppresses the onset of neuromuscular degeneration and increases the life span of mice with familial amyotrophic lateral sclerosis. A mutation of the gene encoding Cu,Zn-superoxide dismutase (SOD1) has been reported in 20% of familial cases of ALS (FALS). L-carnitine effectively inhibits various types of mitochondrial injury and apoptosis both in vitro and in vivo. The present study demonstrates that oral administration of L-carnitine prior to disease onset significantly delayed the onset of signs of disease, delayed deterioration of motor activity, and extended life span. More importantly, subcutaneous injection of L-carnitine increased the life span even when given after the appearance of signs of disease.
20 Mitochondrial Dysfunction PLoS One. 2012;7(4):e Epub 2012 Apr 3. Modulation of astrocytic mitochondrial function by dichloroacetate improves survival and motor performance in inherited amyotrophic lateral sclerosis. Mitochondrial dysfunction is one of the pathogenic mechanisms that lead to neurodegeneration in Amyotrophic Lateral Sclerosis (ALS). Here, we tested the disease-modifying effect of dichloroacetate (DCA), an orphan drug that improves the functional status of mitochondria through the stimulation of the pyruvate dehydrogenase complex activity (PDH). Systemic DCA also decreased astrocyte reactivity and prevented motor neuron loss in SOD1(G93A) mice. Taken together, our results indicate that improvement of the mitochondrial redox status by DCA leads to a disease-modifying effect, further supporting the therapeutic potential of mitochondria-targeted drugs in ALS.
21 Mitochondrial Dysfunction Brain Res Bull Sep 15;89(5-6): doi: /j.brainresbull Mitochondrial dysfunction in human TDP-43 transfected NSC34 cell lines and the protective effect of dimethoxy curcumin. TAR-DNA-binding protein of 43kDa (TDP-43) was recently found to be one of the major disease proteins in the pathological inclusions of amyotrophic lateral sclerosis (ALS). Here, we show that human TDP-43 caused mitochondrial morphologic abnormality, decrease of mitochondrial complex I activity and mitochondrial transmembrane potential, and increased expression of mitochondrial uncoupling protein 2 (UCP2) in human TDP-43 stably transfected NSC-34 cells We also show that dimethoxy curcumin (DMC) could ameliorate mitochondrial dysfunction in mutated TDP-43 stably transfected cell lines. DMC could be potentially useful for neurodegenerative diseases linked with mutated TDP-43.
22 Mitochondrial Dysfunction Mitochondria and ALS: Implications from novel genes and pathways. Mol Cell Neurosci Jun 15. Misfolded SOD1 and ALS: zeroing in on mitochondria. Amyotroph Lateral Scler Jun;13(4): Mitochondrial pathobiology in ALS. J Bioenerg Biomembr Dec;43(6):
23 Ketogenic Diet BMC Neurosci. 2006 Apr 3;7:29. A ketogenic diet as a potential novel therapeutic intervention in amyotrophic lateral sclerosis.The cause of neuronal death in amyotrophic lateral sclerosis (ALS) is uncertain but mitochondrial dysfunction may play an important role. Ketones promote mitochondrial energy production and membrane stabilization.SOD1-G93A transgenic ALS mice were fed a ketogenic diet (KD) based on known formulations for humans. This is the first study showing that diet, specifically a KD, alters the progression of the clinical and biological manifestations of the G93A SOD1 transgenic mouse model of ALS. These effects may be due to the ability of ketone bodies to promote ATP synthesis and bypass inhibition of complex I in the mitochondrial respiratory chain.
24 Ketogenic DietPhase II Safety and Tolerability Study of High Fat/High Calorie Versus High Calorie Versus Optimal Nutrition in Subjects With Amyotrophic Lateral SclerosisMassachusetts General Hospital ClinicalTrials.gov Identifier: NCT54% vs 29% calories from fatWeight loss is a common and severe symptom of amyotrophic lateral sclerosis (ALS), caused both from inadequate calorie intake and an increased metabolic rate. People with ALS are generally instructed to increase their calorie intake; however, the ideal amount and type of calories has not been studied. Several studies in an animal model of motor neuron disease have shown that a high fat/high calorie diet can increase survival by as much as 38%. Mice on a high fat diet also live longer than mice fed diets consisting of high protein or high sugar.
25 Potential Tests24 Urine Toxic Metals plus post-provocative (DMSA) challengeRBC ZincHomocysteineMethylMalonic AcidRBC FolateMTHFR DNA Analysis