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Keywords
AMYOTROPHIC LATERAL SCLEROSIS, VEGF GENE, ANGIOGENIN GENE, SUSCEPTIBILITY GENES, ASSOCIATION STUDIES, NEUROPROTECTION, MOTOR UNIT NUMBER ESTIMATION (MUNE), DISEASE PROGRESSION RATE, GENOTYPE-PHENOTYPE CORRELATION

Hypoxia-induced angiogenetic genes: susceptibility factors to Amyotrophic Lateral Sclerosis ?

Università degli Studi di Siena
Abstract
Amyotrophic lateral sclerosis (ALS) is a progressive and fatal disease characterised by neurodegeneration involving primarily motor neurons of the cerebral cortex, brain stem and spinal cord. The incidence of the disease is about 1-3/100.000/year. . Ninety percent of the cases are sporadic (SALS) and almost 10% are familial (FALS). Approximately 20% of FALS cases and 2% of all ALS cases have identifiable mutations in the SOD1 gene encoding Cu/Zn superoxide dismutase, a major antioxidant enzyme. Thus, pathogenesis of the major part of ALS remains unknown. Recent epidemiological studies indicate that ALS occurrence is growing in many countries, possibly due to environmental factors including trauma to the brain and the spinal cord, strenuous physical activity, exposure to radiation and oxidative toxicity. However these risk factors per se are not be able to cause the disease which rather might reflect a complex interaction between environmental factors and several susceptibility genes. A number of likely candidates gene for ALS as a multifactorial disease, have been proposed. Among “susceptibility” genes potentially contributing to the development of ALS, particular attention has been focused on DNA repair genes. Recent studies have shown that deletion of the hypoxia-responsive element (HRE) in the vascular endothelial growth factor (VEGF) promoter in mice causes motor degeneration reminescent of ALS. Moreover, an association between ALS and some specific VEGF genotypes >>>

Principal Investigator
Fabio Giannini Università degli Studi di SIENA
Research Objectives
Amyotrophic lateral sclerosis (ALS) is a progressive and fatal disease characterised by neurodegeneration involving primarily motor neurons of the cerebral cortex, brain stem and spinal cord. The disease can occur in a familial (FALS) and a sporadic (SALS) form, clinically indistinguishable. In different populations, the frequency of FALS is reported 5-10% of all ALS cases (Brown RH, 1998). Presently four major ALS genes have been identified. In 20% of FALS cases mutations in the gene encoding copper-zinc superoxide dismutase ( SOD1) on chromosome 21q22.1, have been found The other major genes found to cause ALS are: ALSIN, on chromosome 2q33 (SLA2); SETX , on chromosome 9q34 (ALS4); VAPB, on chromosome 20q13.3 (SLA8). Mutations in these three genes have been described only in few and single not European families . The genetic causes of the other 80% forms of FALS are not yet known.
However 90% of all ALS cases are sporadic (SALS) and the pathogenesis of SALS remains largely unknown. It is now widely accepted that SALS is a multi-factorial complex disease, which is attributable to and influenced by the interaction of several as yet unidentified susceptibility genes and environmental factors.
Amomg several hypothesized susceptibility genes, recent data from the literature showed a possible involvement of two genes induced by hypoxia to elicit angiogenesi (VEGF and ANG) in ALS pathogenesis.

The aims of the present Research Project can be summarized >>>

Timescale
12 months
National and international background
Amyotrophic lateral sclerosis (ALS) is a progressive and fatal disease characterised by neurodegeneration involving primarily motor neurons of the cerebral cortex, brain stem and spinal cord resulting in progressive weakness of bulbar, thoracic, abdominal and limb muscles. Other brain functions, as well as oculomotor and sphincter functions, are rarely involved. Mild cognitive impairment is described in 20–50% of cases, while a frontotemporal dementia is reported in 3–5%. Death , due mainly to respiratory failure, occurs 2-4 years after onset, however a small group of patients may have a disease duration of 10 years or even more. The incidence of the disease is about 1-3/100.000/year increasing with age. The disease can occur in familial (FALS) and sporadic (SALS) form, clinically indistinguishable. In different populations, the frequency of FALS is reported 5-10% of all ALS cases (Brown, 1998).
Presently four major ALS genes have been identified. In 20% of FALS cases , over 100 different mutations in the gene encoding copper-zinc superoxide dismutase (SOD1) on chromosome 21q22.1 have been found with an autosomal dominant transmission or, rarely, recessive transmission. The severity of the disease, in terms of age at onset and disease duration, is variable within and between families. Moreover, penetrance may be incomplete and complicated by age dependence so that SOD1 mutation can be identified also in apparently sporadic cases. Genetic testing of SOD1 gene can >>>