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**7** 

**Molecular and Electrical Abnormalities in the** 

Katharina A. Quinlan1, Sherif M. Elbasiouny1 and C.J. Heckman1,2,3 *1Department of Physiology, Northwestern University Feinberg School of Medicine* 

> *2Department of Physical Medicine and Rehabilitation, Northwestern University Feinberg School of Medicine*

> *Northwestern University Feinberg School of Medicine*

*United States of America* 

*3Department of Physical Therapy and Human Movement Sciences,* 

**Mouse Model of Amyotrophic Lateral Sclerosis** 

Amyotrophic lateral sclerosis (ALS) is a devastating, fast progressing and fatal disease for which there is little treatment. It is marked by loss of spinal and cortical motoneuron function. Many parameters are altered in the time leading up to this loss, including electrical properties, endoplasmic reticulum (ER) stress, glial functioning, glutamate signaling, protein degradation, mitochondrial functioning, axonal transport, and immune response. This chapter concentrates on the interplay between altered electrophysiological properties and molecular events. Emphasis is placed on the changes that precede overt symptom onset

Most cases of ALS are spontaneous (sALS), while the heritable form, familial ALS (fALS), represents about 5% of total ALS cases (Byrne et al., 2011). Of fALS patients, 20% have a mutation in the gene that encodes for the superoxide dismutase 1 (SOD1) copper/zinc enzyme (Rosen et al., 1993), 5% have a mutation in the TARDBP gene which encodes DNAbinding protein 43 (TDP-43), another 5% have a mutation in the FUS gene which encodes for the fused in sarcoma FUS/TLS protein (Mackenzie et al., 2010), some possess a mutation in the gene encoding vesicle-associated membrane protein (VAPB) (Nishimura et al., 2004), and a new study shows that some of those remaining have a mutation in the gene coding for the ubiquitin-like protein ubiquilin-2 (Deng et al., 2011). Transgenic mice expressing one of the various mutations of human SOD1, hereafter referred to as SOD1 mice; (Gurney et al., 1994, Bruijn et al., 1997, Zhang et al., 1997) are very common animal models of ALS; numerous other models of fALS are reviewed by Van Den Bosch (2011). It is not known how the SOD1 mutation leads to the degeneration of motoneurons, though it is probably not due to loss of its normal function converting superoxide into hydrogen peroxide. The mutant, misfolded protein likely possesses a toxic gain-of-function, as some mouse lines retain nearly normal levels of SOD1 enzymatic activity and still develop the disease, while SOD1

and results are mainly drawn from studies using the rodent models of ALS.

**1. Introduction** 

**2. ALS animal models** 

