angiogenin and Nerve-Degeneration

Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disorder of the motor neurons in the spinal cord, brainstem, and motor cortex. Ten percent of ALS cases are familial, with both autosomal dominant and recessive modes of inheritance reported. Mutations in the copper/zinc superoxide-dismutase-1 (SOD-1) gene, the first gene linked with ALS, result in the classical ALS phenotype. To date, 135 mutations have been identified in the SOD-1 gene, accounting for approximately 20% of familial ALS cases. Mutations are widely distributed throughout the gene with preponderance for exon 4 and 5. Although mutations result in a toxic gain of function of the SOD-1 enzyme, which normally functions as a free radical scavenger, the mechanisms underlying motor neuron degeneration have not been clearly elucidated. Evidence is emerging of a complex interaction between genetic and molecular factors, with resultant damage of critical target proteins and organelles within the motor neuron. The clinical effectiveness afforded by anti-glutamatergic agents such as riluzole, suggests that glutamate excitotoxicity contributes to neurodegeneration in ALS, with glutamate excitotoxicity mediated via corticomotoneurons that provide a direct link between the motor cortex and the spinal motor neuron. This review provides an overview of the genetics of ALS, and describes recent advances in the understanding of the pathophysiological mechanisms underlying neurodegeneration.

Topics: Amyotrophic Lateral Sclerosis; Animals; Ciliary Neurotrophic Factor; Glutamic Acid; Humans; Intermediate Filament Proteins; Membrane Glycoproteins; Mitochondria; Motor Neurons; Mutation; Nerve Degeneration; Nerve Tissue Proteins; Neurofilament Proteins; Peripherins; Ribonuclease, Pancreatic; Sodium-Potassium-Exchanging ATPase; Superoxide Dismutase; Superoxide Dismutase-1; Survival of Motor Neuron 1 Protein; Vascular Endothelial Growth Factor A

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized clinically by rapidly progressive paralysis leading ultimately to death from respiratory failure. There is substantial evidence suggesting that ALS is a heritable disease, and a number of genes have been identified as being causative in familial ALS. In contrast, the genetics of the much commoner sporadic form of the disease is poorly understood and no single gene has been definitively shown to increase the risk of developing ALS. In this review, we discuss the genetic evidence for each candidate gene that has been putatively associated with increased risk of sporadic ALS. We also review whole genome association studies of ALS and discuss the potential of this methodology for identifying genes relevant to motor neuron degeneration.

Topics: Amyotrophic Lateral Sclerosis; Aryldialkylphosphatase; Cyclic AMP Response Element-Binding Protein; DNA-(Apurinic or Apyrimidinic Site) Lyase; Dynactin Complex; Endosomal Sorting Complexes Required for Transport; Hemochromatosis Protein; Histocompatibility Antigens Class I; Humans; Intercellular Signaling Peptides and Proteins; Intermediate Filament Proteins; Membrane Glycoproteins; Membrane Proteins; Microtubule-Associated Proteins; Nerve Degeneration; Nerve Tissue Proteins; Neurofilament Proteins; Peripherins; Progranulins; Ribonuclease, Pancreatic; RNA-Binding Proteins; SMN Complex Proteins; Superoxide Dismutase; Superoxide Dismutase-1; Vascular Endothelial Growth Factor A

We previously observed marked down-regulation of the mRNA for angiogenin, a potent inducer of neovascularization, in a mouse model of Parkinson's disease (PD) based on over-expression of alpha-synuclein. Angiogenin has also been recently implicated in the pathogenesis of amyotrophic lateral sclerosis. In this study, we confirmed that mouse angiogenin-1 protein is dramatically reduced in this transgenic alpha-synuclein mouse model of PD, and examined the effect of angiogenin in cellular models of PD. We found that endogenous angiogenin is present in two dopamine-producing neuroblastoma cell lines, SH-SY5Y and M17, and that exogenous angiogenin is taken up by these cells and leads to phosphorylation of Akt. Applied angiogenin protects against the cell death induced by the neurotoxins 1-methyl-4-phenylpyridinium and rotenone and reduces the activation of caspase 3. Together our data supports the importance of angiogenin in protecting against dopaminergic neuronal cell death and suggests its potential as a therapy for PD.

Topics: 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; Animals; Cell Death; Cell Line, Tumor; Cytoprotection; Disease Models, Animal; Dopamine; Humans; Mice; Mice, Knockout; Mice, Transgenic; Nerve Degeneration; Neuroblastoma; Neuroprotective Agents; Oncogene Protein v-akt; Parkinsonian Disorders; Phosphorylation; Ribonuclease, Pancreatic

Human angiogenin (ANG) has been highlighted as an angiogenic factor which supports primary and metastatic tumor growth. Recent genetic studies have shown that ANG is presented as a susceptibility gene for amyotrophic lateral sclerosis (ALS) and ALS-frontotemporal dementia (ALS-FTD). They found several missense mutations, including K40I, which present the weakest functional activity in ANG variants. In this study, we investigate whether human wild type ANG (wANG) and its variant K40I (mANG) maintain their divergent functional capacities in neuronal cells. To evaluate this, SH-SY5Y neuroblastoma cells were transfected with wANG and mANG DNA and identified both wild and mutant ANG are localized to nuclei and have no effects on proliferation. We have shown that human wANG prevented cell death under H(2)O(2)-induced oxidative stress in both SH-SY5Y and NSC-34 cells, tested by MTT assay. These effects were more enhanced in motor neuron cell NSC-34. wANG also played a role in cell migration, while mANG decreased these functional activities. Immunoblot analysis revealed that the intracellular signaling of ERK1/2 (at Thr183/Tyr185) was increased following transfection of the wANG gene, and significantly decreased by mANG in neuronal cells. These findings suggest that human ANG plays a critical role in cell protection and migration following alterations in ERK1/2 signaling in SH-SY5Y cells. This may provide the possible relationship between mutations in hANG and other neurodegenerative diseases as well as ALS.

Topics: Animals; Cell Death; Cell Line, Tumor; Cell Movement; Cell Nucleus; Cell Proliferation; Cytoprotection; Dose-Response Relationship, Drug; Humans; Hydrogen Peroxide; Mice; Mitogen-Activated Protein Kinase 1; Mitogen-Activated Protein Kinase 3; Motor Neurons; Mutation; Nerve Degeneration; Neuroblastoma; Oxidants; Oxidative Stress; Ribonuclease, Pancreatic; Signal Transduction; Transfection

Mutations in the Angiogenin gene (ANG) linked to 14q11.2 have been recently discovered to be associated with Amyotrophic Lateral Sclerosis (ALS) in Irish and Scottish populations. In our study we investigated the role of ANG gene in ALS patients from southern Italy. We found a novel mutation in the signal peptide of the ANG gene in a sporadic patient with ALS (SALS). The molecular analysis of the ANG gene also demonstrated an allelic association with the rs11701 single nucleotide polymorphism (SNP) in familial ALS (FALS) but not in SALS patients. Our finding supports the evidence that the ANG gene is involved in ALS.

Topics: Adult; Aged; Amino Acid Substitution; Amyotrophic Lateral Sclerosis; Chromosome Mapping; Chromosomes, Human, Pair 14; Cytoprotection; DNA Mutational Analysis; Female; Genetic Linkage; Genetic Markers; Genetic Predisposition to Disease; Genetic Testing; Humans; Italy; Male; Middle Aged; Motor Neurons; Mutation; Nerve Degeneration; Polymorphism, Single Nucleotide; Ribonuclease, Pancreatic