Amyotrophic Lateral Sclerosis and Metabolomics: Clinical Implication and Therapeutic Approach

Abstract

Amyotrophic lateral sclerosis (ALS) is one of the most common motor neurodegenerative disorders, primarily affecting upper and lower motor neurons in the brain, brainstem, and spinal cord, resulting in paralysis due to muscle weakness and atrophy. The majority of patients die within 3-5 years of symptom onset as a consequence of respiratory failure. Due to relatively fast progression of the disease, early diagnosis is essential. Metabolomics offer a unique opportunity to understand the spatiotemporal metabolic crosstalks through the assessment of body fluids and tissue. So far, one of the most challenging issues related to ALS is to understand the variation of metabolites in body fluids and CNS with the progression of disease. In this paper we will review the changes in metabolic profile in response to disease progression condition and also see the therapeutic implication of various drugs in ALS patients.

Figure 1

(a) Representative serum NMR spectra of control subjects and ALS patients, (b) and (c) show imbalance between oxidative/antioxidant and glutamate/gluatamine cycle. It has been speculated that glutamate excitotoxicty exacerbates the formation of ROS, which may be responsible for the oxidant-antioxidant imbalance, such as increased BHBT and acetone and decreased concentrations of histidine [26].

Figure 2

(a) Schematic diagram of kynurenine pathway. TDO—tryptophan 2,3-dioxygenase, IDO—indoleamine 2,3-dioxygenase, KAT—kynurenine aminotransferase, KZ—kynureninase, HK—kynurenine 3-hydroxylase, HAO—3-hydroxyanthranilate-3,4-dioxygenase, PC—picolinic carboxylase, NC—nonenzymic cyclization. Details are given in the text. (b) Schematic representation of QUIN toxicity in motor neurons. Due to presence of large number of activated glial cells in ALS, there is release of large amount of QUIN into the microenvironment, which can then result in excitotoxicity in motor neurons via NMDA receptors, or it can also be taken up in large quantities by motor neurons. Ultimately, excitotoxicity and the accumulation of QUIN contribute to the demise of motor neurons.