**Part 2**

**Signalling Pathways and Molecular Pathophysiology** 

194 Amyotrophic Lateral Sclerosis

Yi M, Weaver D, Hajnoczky G (2004) Control of mitochondrial motility and distribution by

Zhang B, Tu P, Abtahian F, Trojanowski JQ, Lee VM (1997) Neurofilaments and orthograde

transport are reduced in ventral root axons of transgenic mice that express human

the calcium signal: a homeostatic circuit. J Cell Biol 167:661-672.

SOD1 with a G93A mutation. J Cell Biol 139:1307-1315.

**8** 

*México* 

**Role of Mitochondrial Dysfunction in Motor** 

Luz Diana Santa-Cruz, Uri Nimrod Ramírez-Jarquín and Ricardo Tapia

Amyotrophic lateral sclerosis (ALS), which was described since 1869 by Jean Martin Charcot, is a devastating neurodegenerative disease characterized by the selective and progressive loss of upper and lower motor neurons of the cerebral cortex, brainstem and the spinal cord. Progressive motor neuron loss causes muscle weakness, spasticity and fasciculation, eventually paralysis and finally death by respiratory failure 3 to 5 years after diagnosis. ALS worldwide prevalence is about 2 to 8 people per 100,000, and presents two important differences with respect to other neurogenerative diseases: the cognitive process is not affected and is not merely the result of aging because may occur at young ages (Chancellor & Warlow, 1992; Huisman et al., 2011). Two forms of ALS are known, the familial type (FALS), associated with genetic mutations, mainly in the gene encoding superoxide dismutase 1 (SOD1, enzyme responsible for superoxide dismutation to oxygen and hydrogen peroxide), and the sporadic form (SALS), of unknown origin. FALS represents only about 5-10% of cases (Rosen et al., 1993; Rowland & Shneider, 2001), and SALS comprises the remaining 90%. Despite having different origins, both ALS types

After one hundred fifty years since the first ALS description of the disease, the cause of motor neuron degeneration remains unknown, but progress in neuroscience and clinical research has identified several mechanisms that seem to be involved in the cell death process, such as glutamate-mediated excitotoxicity, inflammatory events, axonal transport

Based on the reduction of glutamate transporter-1 (GLT1 in rodents and excitatory amino acid transporter 2 or EAAT2 in human) content detected post-mortem in motor cortex and spinal cord of ALS patients (Rothstein et al., 1992; Rothstein et al., 1995) and on the increase of glutamate concentration in the cerebrospinal fluid (CSF) of about 40% of ALS patients (Shaw et al., 1995b; Spreux-Varoquaux et al., 2002), one proposed mechanism to explain

develop similar histopathological and clinical characteristics.

deficits, oxidative stress, mitochondrial dysfunction and energy failure.

**2. Mechanisms of motor neuron death in ALS** 

**1. Introduction** 

**2.1 Excitotoxicity** 

**Neuron Degeneration in ALS** 

*División de Neurociencias, Instituto de Fisiología Celular, Universidad Nacional Autónoma de México, México, D.F.,* 
