**SOD1, from Bench to Bed: New Role for the Oldest Protein Implicated in ALS**

Diamanti Luca, Zucchi Elisabetta, Pansarasa Orietta, Ceroni Mauro and Cereda Crisitna

Additional information is available at the end of the chapter

http://dx.doi.org/10.5772/63307

#### **Abstract**

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72 Update on Amyotrophic Lateral Sclerosis

In 1993, the first superoxide dismutase 1 (SOD1) mutation in amyotrophic lateral sclerosis (ALS) patients has been described by Rosen et al. successively, the scientific literature focused on the role of SOD1 in the pathogenesis of ALS. While a clear genetic scenario has been presented, heterogeneous data have been formulated regarding transcriptional and post-transcriptional regulation of SOD1 so far. In particular, the dilemma concerns the SOD1 protein expression, in the direction of a loss of function of the wild-type SOD1 or a toxic gain of function of the altered SOD1, both in FALS (mutant-SOD1) and in SALS (misfolded-SOD1). In this chapter, we focus on the evolution of scientific knowledge about SOD1 protein in ALS patients, reviewing in detail the results obtained using peripheral blood cells in this research field. To conclude, we propose a brief summary of the described clinical correlation and discuss the possible SOD1 implication as a biomarker of ALS.

**Keywords:** trascriptional regulation, post-trascriptional regulation, amyotrophic later‐ al sclerosis (ALS), superoxide dismutase 1 (SOD1), biomarkers, protein aggregation

#### **1. Introduction**

Cu/Zn superoxide dismutase (SOD1) is a 32-KDa homodimeric enzyme that assumes a pivotal role in the scavenging process of the toxic superoxide radicals in the cells [1]. SOD1 is highly expressed in the cytoplasm, but in the 1980s, Chang and colleagues identified SOD1 in other sub-cellular compartments, such as nucleus, lysosomes, and mitochondria [2]. In the 1990s, the scientific literature focused on the genetic and biochemical characterization of SOD1, and in

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1993,Rosenet al.[3]describedthe firstSOD1genemutationassociatedwithamyotrophic lateral sclerosis (ALS) [3]. ALS is an adult-onset neurodegenerative disease that affects selectively cortical, bulbar, and spinal motor neurons, leading invariably to a fatal prognosis. The majori‐ ty of ALS cases (90–95%) are sporadic (SALS), whereas 5–10% are familial (FALS), with genetic mutations dominantly inherited. Among these, more than 150 SOD1 mutations have been reported that are responsible for 20% of FALS, but also 1% of SALS [4]. During the last 20 years, many studies were focused on SOD1 protein in the pathogenesis of ALS, both for FALS and for SALS. Hitherto, some aspects remain unclear: (1) SOD1 alterations give selective loss of motor neurons,eventhoughtheenzymeisubiquitousineverycell;(2)mutationsconferSOD1enzyme's loss of function reducing antioxidant activity but, in some way, mutated enzyme can acquire toxicity;(3)theALS phenotype doesn'treflectthe common presentation ofthe loss-of-functionrelated diseases, in terms of age of onset, clinical spreading, and evolution. In this chapter, we would like to pass through the recent understandings about SOD1 protein in the pathogene‐ sis of ALS, in particular focusing on its aggregation in peripheral blood cells and its transcrip‐ tional/post-transcriptional regulation.
