Disease relevance of Igfals

• Capture of IGFs by ALS is thought to allow the development of a plasma reservoir without negative effects such as hypoglycemia and cell proliferation [1].
• To map the GH response element, a series of 5'-deletion fragments of the mouse ALS promoter (nt -2001 to -49, A(+1)TG) were inserted in the luciferase reporter plasmid pGL3 and transfected into the H4-II-E rat hepatoma cell line [2].
• The benefit of IGF-I in amyotrophic lateral sclerosis ALS and its potential use in preventing motor neuron apoptosis in spinal cord injury dictates that studies of the presence and response of IGFBPs in that tissue be performed [3].
• When mated with an acid-labile subunit (ALS) gene-deleted mouse they also show osteopenia suggesting that circulating IGF-I levels play a significant role in bone formation [4].
• These findings may provide valuable clues about the concurred role of indigenous oxidative stress and exogenous agents in the etiology of sporadic ALS and several other neurodegenerative diseases in which a specific subset of neurons is affected [5].

Psychiatry related information on Igfals

• BMAA has been proposed to be the exogenous excitotoxin in Guam disease or amyotrophic lateral sclerosis (ALS/parkinsonian/dementia; Guam ALS-PD) [6].

High impact information on Igfals

• Lack of apoptosis in mice with ALS [7].
• In serum, the majority of the IGFs exist in a 150-kDa complex including the IGF molecule, IGF binding protein 3 (IGFBP-3), and the acid labile subunit (ALS) [8].
• Liver IGF-1-deficient (LID) mice and ALS knockout (ALSKO) mice exhibited relatively normal growth and development, despite having 75% and 65% reductions in serum IGF-1 levels, respectively [8].
• Thus, the double gene disruption LID+ALSKO mouse model demonstrates that a threshold concentration of circulating IGF-1 is necessary for normal bone growth and suggests that IGF-1, IGFBP-3, and ALS play a prominent role in the pathophysiology of osteoporosis [8].
• Thus, triggering of a motoneuron-restricted cell death pathway by neighboring cells might contribute to motoneuron loss in ALS [9].

Chemical compound and disease context of Igfals

• Within 7 days post-AL, ALS/Lt mice exhibited hyperglycemia and hypoinsulinemia, whereas ALR/Lt mice maintained normal plasma insulin and glucose levels [10].
• To evaluate the causative role of environmental aluminum (Al) in the development of neurodegeneration in Kiiamyotrophic lateral sclerosis (ALS), we examined how chronic exposure to a low-Ca/Mg and high-Al diet induced neuronal loss and tau-related neuronal degeneration in experimental animals [11].

Biological context of Igfals

• Surprisingly, absence of ALS did not affect glucose and insulin homeostasis [1].
• First, the mouse ALS gene was isolated and shown to be organized into two exons and a single intron on chromosome 17 [12].
• Finally, the ALS gene was mapped to mouse chromosome 17 by fluorescence in situ hybridization [13].
• The adult liver is the main source of circulating insulinlike growth factors (IGFs) and their serum binding proteins (IGFBPs) including the acid-labile subunit (ALS), a component of the ternary binding protein complex [14].
• Identical results were obtained when transfections and mobility shift assays were performed in primary rat hepatocytes in which the endogenous ALS gene is expressed [2].

Anatomical context of Igfals

• Here we report three additional genes, Nubp2, Igfals, and Jsap1, that show 50%-methylated CpG sites by Southern blot analyses and primarily monoallelic expression in single-cell allele-specific RT-PCR analysis of bone marrow stromal cells and hepatocytes [15].
• These findings suggest a non-cell-autonomous mechanism through which inflammation could hasten motor neuron death and contribute to the selective motor neuronal degeneration in ALS [16].
• ALS is a fatal paralytic disorder characterized by a progressive loss of spinal cord motor neurons [16].
• Finally, an ALS knockout model was created by inactivating the ALS gene in mouse embryonic stem cells [12].
• Expression of ALS was localized in hepatocytes only [14].

Associations of Igfals with chemical compounds

• By immunization with N-terminal and C-terminal specific ALS oligopeptides, we generated monoclonal antibodies (mAbs) that target ALS-specific sequences outside the nonspecific leucine-rich repeats in the ALS molecule [17].
• INTERPRETATION: The previously documented role of Cox-2 in ALS neurodegeneration in this particular mouse model occurs through a mechanism independent of prostaglandin E(2) [18].
• Cultured ALS/Lt islets exposed for 5 min to increasing (0-3 mmol/l) AL concentrations in vitro exhibited an 80% decline in numbers of intact islets after a subsequent 6-day culture period, as well as a 75% reduction in islet insulin content and a 94% decrease in glucose-stimulated insulin secretory capacity [10].
• However, pretreatment of the latter two strains with appropriate doses of either x-irradiation (150 R), cyclophosphamide (100 mg/kg) or ALS (150 mul) before carrier-preimmunization strikingly enhances the magnitude of IgE antibody responses in such mice to levels as high as 64-fold above those of untreated control mice of the same strains [19].
• These manipulations included the use of pretransplant donor-specific transfusion, administration of ALS or cyclosporin-A, or the use of posttransplant injection with a T suppressor activating factor (SAF) [20].

Physical interactions of Igfals

• The activation of the mouse ALS gene by GH is mediated by the binding of STAT5 isoforms to this sequence [12].

Other interactions of Igfals

• Consequently, Peg-induced GH deficiency in WT mice severely reduced ALS, IGF-I, and IGFBP-3 in the circulation and caused a severe growth deficit [21].
• Herein, we show that NADPH oxidase, the main reactive oxygen species-producing enzyme during inflammation, is activated in spinal cords of ALS patients and in spinal cords in a genetic animal model of this disease [16].
• This growth depression is associated with large decreases in the plasma concentrations of both IGF-I and IGFBP-3, indicating the critical role of ALS in the regulation of circulating levels of these proteins [12].
• The present study provides the first evidence that IGF-I receptor immunoreactivity was increased in reactive astrocytes in the central nervous system of SOD(G93A) transgenic mice, suggesting that reactive astrocytes may play an important role in the pathogenesis and progress of ALS [22].
• In addition, reduced hepatic mRNA levels of ALS and GHR in B6 suggests hepatic GH resistance in B6 [23].

Analytical, diagnostic and therapeutic context of Igfals

• Monoclonal anti-acid-labile subunit oligopeptide antibodies and their use in a two-site immunoassay for ALS measurement in humans [17].
• METHODS: To generate an alsin loss-of-function model in an ALS-relevant cell type, we developed a new small interfering RNA electroporation technique that allows efficient knock down of alsin in embryonic rat spinal motoneurons [24].
• Specific unresponsiveness to skin allografts can be induced in ALS-treated mice by the injection of bone marrow from the graft-donor strain [25].
• Immune deficiency, however, resulting from neonatal thymectomy or long term ALS administration led A/J animals to remain susceptible when tested at adult age [26].
• Lymphoid cells were isolated from mouse mammary tumors by isokinetic gradient centrifugation. theta-bearing and ALS-sensitive cells were always the largest subpopulations found in these tumors [27].

References