A Fork in the Road: Angiogenin Predisposes to ALS and Parkinson’s

The angiogenin gene has been linked to amyotrophic lateral sclerosis (ALS) for years, but a study in the Annals of Neurology adds a new wrinkle: These variants are just as likely to cause Parkinson’s disease. The authors of the international, multisite report—posted online August 17—are not sure what causes one person with abnormal angiogenin to suffer motor neuron disease, while others develop parkinsonism. Angiogenin is a neuroprotective factor, and based on this research, it might someday be a treatment not only for ALS, but also for Parkinson’s.

Angiogenin variants are so rare that not all studies have shown the gene associated with ALS, said Amelie Gubitz, program director for neurodegeneration at the National Institute of Neurological Disorders and Stroke in Bethesda, Maryland. “It is one of those risk factors that still had a question mark,” she said. And since it is a risk factor that does not always cause disease, the fact that some healthy people possess angiogenin mutations has added further uncertainty to the gene’s role in neurodegeneration (see ARF related news story on Greenway et al., 2006; reviewed in Schymick et al., 2007). The new study, she said, helps clinch the angiogenin ALS link even as it expands the gene’s influence to Parkinson’s.

First author Michael van Es and senior author Leonard van den Berg, both at the University Medical Center Utrecht, The Netherlands, previously reported on a family in which several members carried an angiogenin mutation (van Es et al., 2009). Many, but not all, members with the angiogenin variant developed ALS. But one person in the pedigree was initially diagnosed with Parkinson’s disease. Other data have also linked ALS and Parkinson’s. For example, motor neuron disease and parkinsonism coincide in a condition unique to the Chamorro people of Guam (Hirano et al., 1966). And family members of people with ALS are at higher-than-normal risk for Parkinson’s (Majoor-Krakauer et al., 1994).

Intrigued, the researchers screened people with Parkinson’s for angiogenin mutations and found variants in the gene in approximately 1 percent of them. Co-senior author John Landers, of the University of Massachusetts Medical School in Worcester, had a similar idea. The groups joined forces, along with co-senior author Bart van de Warrenburg of the Radboud University Nijmegen Medical Center in The Netherlands, to perform the “largest, and therefore best study” possible, van Es told ARF in an e-mail. The researchers teamed with 52 other scientists across Europe and the U.S. to amass angiogenin sequences from both previously published studies and from new subjects. In total, the scientists analyzed the gene from 3,146 people with Parkinson’s, 6.471 with ALS, and 7,688 healthy control subjects.

Given the rarity of angiogenin variants, finding them required such a large collaboration, Gubitz said. Even among people with PD or ALS, angiogenin variants showed up in fewer than half a percent of participants. The team identified 27 angiogenin mutations that were found more often in people with neurodegeneration than in control participants. Compared to control subjects, people with ALS were more than nine times as likely to have an angiogenin mutation; those with Parkinson’s were nearly sevenfold more likely to carry an angiogenin variant.

“Angiogenin mutations are found in nearly equal frequencies in ALS and PD patients, with comparable odds ratios,” van Es wrote. “So I do not think angiogenin mutations are more relevant to one disease or the other.” He suspects that additional, unknown genetic factors might sway a person toward ALS or Parkinson’s. Environmental risks could also contribute, Gubitz suggested.

Angiogenin is not the first genetic risk factor to cross the borders between neurodegenerative diseases. For example, tau is linked to frontotemporal dementia as well as Parkinson’s (Subramanian et al., 2008). And an excess of genetic repeats in ataxin-2 can appear in either ALS or spinocerebellar ataxia (see ARF related news story on Elden et al., 2010), and may contribute to Parkinson’s as well (Payami et al., 2003).

“Perhaps there are some shared cellular disease pathways that we could exploit” in research and therapies, Gubitz suggested. Angiogenin protects neurons by blocking apoptosis. The variants tend to cause loss of function, van Es wrote, making cells more susceptible to programmed cell death (Wu et al., 2007; Subramanian, 2008). Could replacing angiogenin fix the problem? Researchers such as study co-author Guo-fu Hu, of Tufts Medical Center in Boston, are already testing the effects of angiogenin treatment in a mouse model of ALS (see ARF related news story on Li et al., 2011; also Kieran et al., 2008).—Amber Dance

Comments

  1. This is an interesting paper based on a longstanding hypothesis in the field that different neurodegenerative diseases may have common or overlapping etiologies. Here, more evidence is presented suggesting this may indeed be the case. Such links are intriguing, as they suggest that common therapeutic pathways may exist as well.

    View all comments by Katrina Gwinn

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References

News Citations

  1. ALS—Study Strengthens VEGF Connection, Potential Biomarkers Proffered
  2. ALS—A Polyglutamine Disease? Mid-length Repeats Boost Risk
  3. Trichostatin A, Angiogenin Keep Neurons Alive in ALS

Paper Citations

  1. Greenway MJ, Andersen PM, Russ C, Ennis S, Cashman S, Donaghy C, Patterson V, Swingler R, Kieran D, Prehn J, Morrison KE, Green A, Acharya KR, Brown RH, Hardiman O. ANG mutations segregate with familial and 'sporadic' amyotrophic lateral sclerosis. Nat Genet. 2006 Apr;38(4):411-3. PubMed.
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  3. van Es MA, Diekstra FP, Veldink JH, Baas F, Bourque PR, Schelhaas HJ, Strengman E, Hennekam EA, Lindhout D, Ophoff RA, van den Berg LH. A case of ALS-FTD in a large FALS pedigree with a K17I ANG mutation. Neurology. 2009 Jan 20;72(3):287-8. PubMed.
  4. Hirano A, Malamud N, Elizan TS, Kurland LT. Amyotrophic lateral sclerosis and Parkinsonism-dementia complex on Guam. Further pathologic studies. Arch Neurol. 1966 Jul;15(1):35-51. PubMed.
  5. Majoor-Krakauer D, Ottman R, Johnson WG, Rowland LP. Familial aggregation of amyotrophic lateral sclerosis, dementia, and Parkinson's disease: evidence of shared genetic susceptibility. Neurology. 1994 Oct;44(10):1872-7. PubMed.
  6. Subramanian V, Crabtree B, Acharya KR. Human angiogenin is a neuroprotective factor and amyotrophic lateral sclerosis associated angiogenin variants affect neurite extension/pathfinding and survival of motor neurons. Hum Mol Genet. 2008 Jan 1;17(1):130-49. PubMed.
  7. Elden AC, Kim HJ, Hart MP, Chen-Plotkin AS, Johnson BS, Fang X, Armakola M, Geser F, Greene R, Lu MM, Padmanabhan A, Clay-Falcone D, McCluskey L, Elman L, Juhr D, Gruber PJ, Rüb U, Auburger G, Trojanowski JQ, Lee VM, Van Deerlin VM, Bonini NM, Gitler AD. Ataxin-2 intermediate-length polyglutamine expansions are associated with increased risk for ALS. Nature. 2010 Aug 26;466(7310):1069-75. PubMed.
  8. Payami H, Nutt J, Gancher S, Bird T, McNeal MG, Seltzer WK, Hussey J, Lockhart P, Gwinn-Hardy K, Singleton AA, Singleton AB, Hardy J, Farrer M. SCA2 may present as levodopa-responsive parkinsonism. Mov Disord. 2003 Apr;18(4):425-9. PubMed.
  9. Wu D, Yu W, Kishikawa H, Folkerth RD, Iafrate AJ, Shen Y, Xin W, Sims K, Hu GF. Angiogenin loss-of-function mutations in amyotrophic lateral sclerosis. Ann Neurol. 2007 Dec;62(6):609-17. PubMed.
  10. Li S, Yu W, Hu GF. Angiogenin inhibits nuclear translocation of apoptosis inducing factor in a Bcl-2-dependent manner. J Cell Physiol. 2011 Jun 15; PubMed.
  11. Kieran D, Sebastia J, Greenway MJ, King MA, Connaughton D, Concannon CG, Fenner B, Hardiman O, Prehn JH. Control of motoneuron survival by angiogenin. J Neurosci. 2008 Dec 24;28(52):14056-61. PubMed.

Further Reading

Papers

  1. Cho GW, Kang BY, Kim SH. Human angiogenin presents neuroprotective and migration effects in neuroblastoma cells. Mol Cell Biochem. 2010 Jul;340(1-2):133-41. PubMed.
  2. Crabtree B, Thiyagarajan N, Prior SH, Wilson P, Iyer S, Ferns T, Shapiro R, Brew K, Subramanian V, Acharya KR. Characterization of human angiogenin variants implicated in amyotrophic lateral sclerosis. Biochemistry. 2007 Oct 23;46(42):11810-8. PubMed.
  3. Seilhean D, Cazeneuve C, Thuriès V, Russaouen O, Millecamps S, Salachas F, Meininger V, LeGuern E, Duyckaerts C. Accumulation of TDP-43 and alpha-actin in an amyotrophic lateral sclerosis patient with the K17I ANG mutation. Acta Neuropathol. 2009 Oct;118(4):561-73. PubMed.
  4. Bosco DA, Landers JE. Genetic determinants of amyotrophic lateral sclerosis as therapeutic targets. CNS Neurol Disord Drug Targets. 2010 Dec;9(6):779-90. PubMed.
  5. Gilbert RM, Fahn S, Mitsumoto H, Rowland LP. Parkinsonism and motor neuron diseases: twenty-seven patients with diverse overlap syndromes. Mov Disord. 2010 Sep 15;25(12):1868-75. PubMed.

Primary Papers

  1. van Es MA, Schelhaas HJ, van Vught PW, Ticozzi N, Andersen PM, Groen EJ, Schulte C, Blauw HM, Koppers M, Diekstra FP, Fumoto K, Leclerc AL, Keagle P, Bloem BR, Scheffer H, van Nuenen BF, van Blitterswijk M, van Rheenen W, Wills AM, Lowe PP, Hu GF, Yu W, Kishikawa H, Wu D, Folkerth RD, Mariani C, Goldwurm S, Pezzoli G, Van Damme P, Lemmens R, Dahlberg C, Birve A, Fernández-Santiago R, Waibel S, Klein C, Weber M, van der Kooi AJ, de Visser M, Verbaan D, van Hilten JJ, Heutink P, Hennekam EA, Cuppen E, Berg D, Brown RH, Silani V, Gasser T, Ludolph AC, Robberecht W, Ophoff RA, Veldink JH, Pasterkamp RJ, de Bakker PI, Landers JE, van de Warrenburg BP, van den Berg LH. Angiogenin variants in Parkinson disease and amyotrophic lateral sclerosis. Ann Neurol. 2011 Dec;70(6):964-73. PubMed.

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