angiogenin and Parkinson-Disease

In this review, we summarise the evidence for a role of the ribonuclease angiogenin in the pathophysiology of neurodegenerative disorders, with a specific focus on Parkinson's disease (PD). Angiogenin is a stress-induced, secreted ribonuclease with both nuclear and cytosolic activities. Loss-of-function mutations in the angiogenin gene (ANG) have been initially discovered in familial cases of amyotrophic lateral sclerosis (ALS), however, variants in ANG have subsequently been identified in PD and Alzheimer's disease. Delivery of angiogenin protein reduces neurodegeneration and delays disease progression in in vitro and in vivo models of ALS and in vitro models of PD. In the nucleus, angiogenin promotes ribosomal RNA transcription. Under stress conditions, angiogenin also translocates to the cytosol where it cleaves non-coding RNA into RNA fragments, in particular transfer RNAs (tRNAs). Stress-induced tRNA fragments have been proposed to have multiple cellular functions, including inhibition of ribosome biogenesis, inhibition of protein translation and inhibition of apoptosis. We will discuss recent evidence of tRNA fragment accumulation in PD, as well as their potential neuroprotective activities.

Topics: Animals; Humans; Parkinson Disease; Ribonuclease, Pancreatic; RNA, Transfer

Parkinson's disease (PD) is the second most common form of neurodegeneration among the elderly population. PD is clinically characterized by tremors, rigidity, slowness of movement, and postural imbalance. Interestingly, a significant association has been demonstrated between PD and low levels of vitamin D in the serum, and vitamin D supplement appears to have a beneficial clinical effect on PD. Genetic studies have provided the opportunity to determine which proteins link vitamin D to PD pathology, e.g., Nurr1 gene, toll-like receptor, gene related to lipid disorders, vascular endothelial factor, tyrosine hydroxylase, and angiogenin. Vitamin D also exerts its effects on cancer through nongenomic factors, e.g., bacillus Calmette-Guerin vaccination, interleukin-10, Wntβ-catenin signaling pathways, mitogen-activated protein kinase pathways, and the reduced form of the nicotinamide adenine dinucleotide phosphate. In conclusion, vitamin D might have a beneficial role in PD. Calcitriol is best used for PD because it is the active form of the vitamin D(3) metabolite and modulates inflammatory cytokine expression. Further investigation with calcitriol in PD is needed.

Topics: Animals; BCG Vaccine; Calcitriol; Cholesterol; Genetic Association Studies; Humans; Hypercalcemia; Mice; Mice, Knockout; NADPH Oxidases; Nuclear Receptor Subfamily 4, Group A, Member 2; Parkinson Disease; Parkinsonian Disorders; Rats; Receptors, Calcitriol; Ribonuclease, Pancreatic; Signal Transduction; Toll-Like Receptors; Tyrosine 3-Monooxygenase; Vascular Endothelial Growth Factor A; Vitamin D; Vitamin D Deficiency

Several studies have suggested an increased frequency of variants in the gene encoding angiogenin (ANG) in patients with amyotrophic lateral sclerosis (ALS). Interestingly, a few ALS patients carrying ANG variants also showed signs of Parkinson disease (PD). Furthermore, relatives of ALS patients have an increased risk to develop PD, and the prevalence of concomitant motor neuron disease in PD is higher than expected based on chance occurrence. We therefore investigated whether ANG variants could predispose to both ALS and PD.. We reviewed all previous studies on ANG in ALS and performed sequence experiments on additional samples, which allowed us to analyze data from 6,471 ALS patients and 7,668 controls from 15 centers (13 from Europe and 2 from the USA). We sequenced DNA samples from 3,146 PD patients from 6 centers (5 from Europe and 1 from the USA). Statistical analysis was performed using the variable threshold test, and the Mantel-Haenszel procedure was used to estimate odds ratios.. Analysis of sequence data from 17,258 individuals demonstrated a significantly higher frequency of ANG variants in both ALS and PD patients compared to control subjects (p = 9.3 × 10(-6) for ALS and p = 4.3 × 10(-5) for PD). The odds ratio for any ANG variant in patients versus controls was 9.2 for ALS and 6.7 for PD.. The data from this multicenter study demonstrate that there is a strong association between PD, ALS, and ANG variants. ANG is a genetic link between ALS and PD.

Topics: Amyotrophic Lateral Sclerosis; Databases, Factual; Europe; Female; Genetic Predisposition to Disease; Genetic Variation; Humans; Male; Multicenter Studies as Topic; Parkinson Disease; Ribonuclease, Pancreatic; United States

Human Angiogenin (hANG, or ANG, 14.1 kDa) promotes vessel formation and is also called RNase 5 because it is included in the pancreatic-type ribonuclease (pt-RNase) super-family. Although low, its ribonucleolytic activity is crucial for angiogenesis in tumor tissues but also in the physiological development of the Central Nervous System (CNS) neuronal progenitors. Nevertheless, some ANG variants are involved in both neurodegenerative Parkinson disease (PD) and Amyotrophic Lateral Sclerosis (ALS). Notably, some pt-RNases acquire new biological functions upon oligomerization. Considering neurodegenerative diseases correlation with massive protein aggregation, we analyzed the aggregation propensity of ANG and of three of its pathogenic variants, namely H13A, S28N, and R121C. We found no massive aggregation, but wt-ANG, as well as S28N and R121C variants, can form an enzymatically active dimer, which is called ANG-D. By contrast, the enzymatically inactive H13A-ANG does not dimerize. Corroborated by a specific cross-linking analysis and by the behavior of H13A-ANG that in turn lacks one of the two His active site residues necessary for pt-RNases to self-associate through the three-dimensional domain swapping (3D-DS), we demonstrate that ANG actually dimerizes through 3D-DS. Then, we deduce by size exclusion chromatography (SEC) and modeling that ANG-D forms through the swapping of ANG N-termini. In light of these novelties, we can expect future investigations to unveil other ANG determinants possibly related with the onset and/or development of neurodegenerative pathologies.

Topics: Amyotrophic Lateral Sclerosis; Chromatography; Crystallography, X-Ray; Dimerization; Genetic Variation; Humans; Models, Molecular; Mutation; Parkinson Disease; Phosphorylation; Protein Conformation; Protein Domains; Ribonuclease, Pancreatic; Ribonucleases; Sulfones

Genetic risk factors are occasionally shared between different neurodegenerative diseases. Previous studies have linked ANG, a gene encoding angiogenin, to both Parkinson's disease (PD) and amyotrophic lateral sclerosis (ALS). Functional studies suggest ANG plays a neuroprotective role in both PD and amyotrophic lateral sclerosis by reducing cell death. We further explored the genetic association between ANG and PD by analyzing genotype data from the International Parkinson's Disease Genomics Consortium (14,671 cases and 17,667 controls) and whole genome sequencing data from the Accelerating Medicines Partnership - Parkinson's disease initiative (AMP-PD, https://amp-pd.org/) (1,647 cases and 1,050 controls). Our analysis did not replicate the findings of previous studies and identified no significant association between ANG variants and PD risk.

Topics: Amyotrophic Lateral Sclerosis; Cell Death; Genetic Variation; Genome-Wide Association Study; Genotype; Humans; Parkinson Disease; Ribonuclease, Pancreatic; Risk Factors; Whole Genome Sequencing

Mutations in Angiogenin (ANG), a member of the Ribonuclease A superfamily (also known as RNase 5) are known to be associated with Amyotrophic Lateral Sclerosis (ALS, motor neurone disease) (sporadic and familial) and Parkinson's Disease (PD). In our previous studies we have shown that ANG is expressed in neurons during neuro-ectodermal differentiation, and that it has both neurotrophic and neuroprotective functions. In addition, in an extensive study on selective ANG-ALS variants we correlated the structural changes to the effects on neuronal survival and the ability to induce stress granules in neuronal cell lines. Furthermore, we have established that ANG-ALS variants which affect the structure of the catalytic site and either decrease or increase the RNase activity affect neuronal survival. Neuronal cell lines expressing the ANG-ALS variants also lack the ability to form stress granules. Here, we report a detailed experimental structural study on eleven new ANG-PD/ALS variants which will have implications in understanding the molecular basis underlying their role in PD and ALS.

Topics: Amyotrophic Lateral Sclerosis; Crystallography, X-Ray; Genetic Variation; Humans; Mutant Proteins; Mutation; Parkinson Disease; Protein Conformation; Ribonuclease, Pancreatic

Topics: Adult; Aged; Aged, 80 and over; Amyotrophic Lateral Sclerosis; Case-Control Studies; Female; Humans; Male; Middle Aged; Parkinson Disease; Ribonuclease, Pancreatic; Young Adult

Mutations in the angiogenic factor, angiogenin (ANG), have been identified in patients with both familial and sporadic amyotrophic lateral sclerosis (ALS) and are thought to have a neuroprotective function. Parkinsonism has been noted in kindreds with ANG mutations and variants in the ANG gene have been found to associate with PD in two Caucasian populations. We therefore hypothesized that mutations in ANG may also contribute to idiopathic Parkinson's disease (PD). We sequenced ANG gene in a total of 1498 participants comprising 750 PD patients and 748 age/gender matched controls from Taiwan. We identified one novel synonymous substitution, c.C100T (p.L10L), in a single heterozygous state in one PD patient, which was not observed in controls. The clinical phenotypes and [99mTc]-TORDAT-SPECT images of the p.L10L carrier were similar to that seen in idiopathic PD. In addition, we also identified one common variant, c.T330G (p.G110G, rs11701), which was previously reported to associate with PD risk in Caucasians. However, the frequency of TG/GG genotype was comparable between PD cases and controls (odds ratio: 0.85, 95% confidence interval: 0.29-2.55, P = 0.78). Our results did not support that ANG rs11701 variant is a genetic risk factor for PD in our population. We conclude that mutations in ANG are not a common cause for idiopathic PD.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Asian People; Case-Control Studies; DNA Mutational Analysis; Female; Gene Frequency; Genetic Predisposition to Disease; Heterozygote; Humans; Male; Middle Aged; Mutation; Parkinson Disease; Polymorphism, Single Nucleotide; Ribonuclease, Pancreatic; Taiwan; Young Adult

The angiogenic factor, angiogenin, has been recently linked to both Amyotrophic Lateral Sclerosis (ALS) and Parkinson Disease (PD). We have recently shown that endogenous angiogenin levels are dramatically reduced in an alpha-synuclein mouse model of PD and that exogenous angiogenin protects against cell loss in neurotoxin-based cellular models of PD. Here, we extend our studies to examine whether activation of the prosurvival Akt pathway is required for angiogenin's neuroprotective effects against 1-methyl-4-phenylpyridinium (MPP+), as observed in ALS models, and to test the effect of virally-mediated overexpression of angiogenin in an in vivo PD model. Using a dominant negative Akt construct, we demonstrate that inhibition of the Akt pathway does not reduce the protective effect of angiogenin against MPP+ toxicity in the dopaminergic SH-SY5Y cell line. Furthermore, an ALS-associated mutant of angiogenin, K40I, which fails to induce Akt phosphorylation, was similar to wildtype angiogenin in protection against MPP+. These results confirm previous work showing neuroprotective effects of angiogenin against MPP+, and indicate that Akt is not required for this protective effect. We also investigated whether adeno-associated viral serotype 2 (AAV2)-mediated overexpression of angiogenin protects against dopaminergic neuron loss in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mouse model. We found that angiogenin overexpression using this approach does not reduce the MPTP-induced degeneration of dopaminergic cells in the substantia nigra, nor limit the depletion of dopamine and its metabolites in the striatum. Together, these findings extend the evidence for protective effects of angiogenin in vitro, but also suggest that further study of in vivo models is required to translate these effects into meaningful therapies.

Topics: 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; Animals; Cell Count; Cell Line, Tumor; Dependovirus; Disease Models, Animal; Dopamine; Dopaminergic Neurons; Gene Expression; Humans; Male; Mice; Mice, Inbred C57BL; Mutation; Neostriatum; Parkinson Disease; Phosphatidylinositol 3-Kinases; Phosphorylation; Proto-Oncogene Proteins c-akt; Ribonuclease, Pancreatic; Signal Transduction; Substantia Nigra

Recently, the angiogenin gene has been reported to be significantly associated with Parkinson's disease and amyotrophic lateral sclerosis in populations of European and American ancestry. But there have been no studies investigating the association between angiogenin and Parkinson's disease in the ethnic Chinese population. We conducted a case-control study to evaluate the association between angiogenin and Parkinson's disease in a Chinese population from mainland China. We sequenced the exons of angiogenin in 532 Parkinson's disease patients and 480 controls. We did not detect an angiogenin coding region mutation in either the patients or the controls. Our data do not support the association of angiogenin variants with PD in Han Chinese of mainland China.

Topics: Adult; Aged; Aged, 80 and over; Asian People; Case-Control Studies; China; DNA Mutational Analysis; Ethnicity; Female; Genetic Association Studies; Genetic Predisposition to Disease; Genetic Variation; Humans; Male; Middle Aged; Parkinson Disease; Reverse Transcriptase Polymerase Chain Reaction; Ribonuclease, Pancreatic; Young Adult