The Lesson We Can Learn from Familial ALS Patients Carrying a SOD1 Mutation

Amyotrophic Lateral Sclerosis (ALS) is a neurodegenerative disease causing progressive death of the motor neurons in both brain cortex and spinal cord. Twenty per cent of ALS familial cases (fALS) are caused by a mutation in the SOD1 gene. The SOD1 gene is located in the short arm of human chromosome 21 and consists of 5 exons encoding for 153 amino acids. More than 100 mutations have been identified that are spred in all parts of the SOD1 gene; the majority of them are missense mutations but there are both insertions and deletions. Two mutations, in 126 and 141 codons, define a signal stop that produces a shorter protein. Mutations have been found also in intronic parts of the gene in two ALS cases. All mutations behave as autosomal dominant traits except for the D90A and the L84F, that exist in both dominant and recessive forms. Attempts to correlate genotype with phenotype demonstrated that prediction of disease severity based on age of onset and disease duration on the basis of the single SOD1 mutation remains uncertain. Some mutations are associated with early onset (L38V, G37S), while others are associated with particularly short (A4V) or relatively long (D100G) disease duration. Mutations in SOD1 gene were also found in ALS patients with no family history. Subjects with SOD1 mutations (L84F, L144F and D76V) that did not develop the disease were reported. Epidemiological data underline that, in some cases, a mutation is present only in a single population: A4T mutation in the Japanese population, D76V in the hispanic one, the L144F mutation in several patients coming from Slavic regions (Yugoslavia, Croatia). Correlation between sex, regional disease onset, age of onset and SOD1 gene mutations have not been found. SOD1 mutations have been divided in three groups considering the three-dimensional structure of the wt protein. One group of mutations occurs within the dimer interface (A4V), while another group is positioned in loop regions at the end of beta ƒ{strands (G93A). Mutant proteins falling into these two groups appear to have full SOD1 activity and biophysical properties similar to the wt SOD1 protein. The third group of mutations is located near the metal binding site, in particular the protein region that binds copper ion. These mutant proteins (H46R, H48Q) carry little amount of copper or zinc and have biophysical properties quite different from the wt SOD1 protein. In fALS carrying a SOD1 mutation the mutated protein is the cause for the development of ALS. In fALS various mutated SOD1 proteins show unaltered enzymatic activity, thus suggesting that the mutations in SOD1 gene may act causing a toxic ¡§gain of function¡¨ in SOD1 rather than a loss of function. In fALS SOD1 accumulates within the cytoplasm of the motor neurons. Similarly in sporadic ALS, intracellular aggregates in motor neurons have been found, possibly containing SOD1. As ALS, several other neurodegenerative disorders, like Alzheimer¡¦s disease, Parkinson¡¦s disease and prion diseases, are characterized by the accumulation of specific proteins in the brain areas in which neuronal loss occurs. The majority of neurodegenerative disorders have both familial and sporadic presentation and the gene involved in the familial form encodes for the protein that accumulates in both familial and sporadic form. Moreover, the mutated proteins may function normally, but tend to accumulate in a conformation that hampers degradation (amyloid). While the specific features of each disorder is related to the affected neuronal population and to the protein involved, the common aspect relies in the mechanisms of cell death. In fact, many experimental data demonstrate that in neurodegenerative disorders a common apoptotic mechanism causes the neuronal death through the activation of different factors (such as cdk5, Apaf-1 and JNK) belonging to the same pathway. We think that the neuronal cell peculiar condition of being unable to replicate is of fundamental importance in understanding neurodegeneration. In the CNS the condition of permanent neuronal cells throughout the individual life span exists only by the strict interaction between neurons and glial cells. In ALS peripheral blood cells express mutated SOD1 and display alterations in mitochondrial metabolism and calcium homeostasis, but they show no degeneration. In our hypothesis neurodegenerative diseases are the expression of a general difficulty in degradation of misfolded proteins that are toxic to the cell. Whereas replicating tissues can resolve such problem by replacing itscellular components, nervous tissue can not. This is the reason why only neurons contain the aggregated protein. This could also explain why neurodegeneration and aging are so closely related.