27 Dec 2010

The human genome is littered with scraps of millennia-old retroviruses, which hopped in, never hopped back out, and now pass from parents to children. Some of those retroviruses may wake up and contribute to amyotrophic lateral sclerosis, according to researchers at Johns Hopkins University in Baltimore, Maryland. Their paper was accepted November 8 by the Annals of Neurology and is available online. If confirmed, the results suggest that retroviral genes and proteins could be a useful biomarker for ALS.

First author Renée Douville, who has since moved to the Lady Davis Institute in Montréal, Canada, led the research in the Johns Hopkins laboratory of senior author Avindra Nath. She hunted down the retroviral gene pol, which encodes reverse transcriptase, in a collection of frozen brain samples: 28 cases of ALS (25 sporadic, three familial); 12 cases of chronic systemic disease such as coronary artery disease or cancer; 10 control cases of accidental death, mostly traffic accidents; and 12 cases of Parkinson’s disease. She found the retrovirus HERV-K was active, to varying levels, in nearly all people who had ALS, plus the chronic disease cases. Viral proteins could have been toxic to neurons or upset cellular metabolism, Nath suggested. However, he noted that it is too early to do much more than speculate about the results. “So far, all we have shown is association,” Nath said. “The caveat of all this is it could be a non-specific finding.”

The study is not the first to link ALS and retroviruses. After all, TAR-DNA binding protein 43, currently starring in many an ALS research program, was first identified because it binds the HIV gene TAR (Ou et al., 1995). Scientists have found reverse transcriptase in serum from people with ALS before (MacGowan et al., 2007; McCormick et al., 2008), and hunted for evidence of infectious environmental viruses such as HIV, which can cause ALS-like symptoms (see ARF related news story on MacGowan et al., 2001 and Moulignier et al., 2001; also Verma and Berger, 2006). “They never found anything,” Nath said. Instead, he and Douville sought evidence of endogenous retroviruses, which jumped into human DNA and stayed put millions of years ago (reviewed in Bannert and Kurth, 2006). “Nine percent of the human genome is retroviral sequences,” Nath said.

Nath studies neurological complications of retroviruses such as HIV; he collaborated with Jeffrey Rothstein, an ALS researcher in the laboratory next door, who provided the brain tissue. Douville screened mRNAs, via RT-PCR, with a handful of primers for endogenous retroviral pol. She found that HERV-K pol was transcribed in the ALS cases—sporadic and familial—as well as the systemic disease samples. PD and accidental death samples did not evince RT pol transcription. HERV-K has also been implicated in multiple sclerosis (Dolei et al., 2009; Perron and Lang, 2010). Although HERV-K was the strongest hit, the researchers note that their findings do not eliminate the possibility that other retroviruses are active, too. HERV-K pol mRNA showed up strongly in the prefrontal and sensory cortex, with less in the motor cortex. Nath suggested this is because so many motor cortex cells have already died. The researchers have not yet examined spinal cord tissue.

Is HERV-K expression a cause of neurodegeneration, or merely the swan song of neurons dying for a different reason? The researchers do not know, Nath said, although he pointed to the lack of HERV-K pol transcription in Parkinson’s cases as evidence that it does not show up in every neurodegenerative disease.

Douville further examined pol expression by immunostaining. Ten of 13 ALS cases were positive for RT, versus three of 10 systemic disease cases. Reverse transcriptase tended to show up in clusters of neurons, in the kind of staining pattern one might expect if the virus were made in one cell and released to attack neighboring neurons, Nath noted. He added that the idea was purely hypothetical.

Dozens of HERV-K sequences are sprinkled throughout the human genome, so the researchers attempted to pinpoint the ALS-related loci by sequencing DNA. They used primers that started in the retroviral genes and followed the sequence through into the native human DNA. They found hits on the seventh chromosome, among others. ALS cases, in particular, expressed pol genes at 7q34 and 7q36.1. Tantalizingly, these loci sit within an unidentified motor neuron disease (MND) locus in the 7q34-7q36 region (Gopinath et al., 2007); Douville and Nath suggest the unknown ALS gene could be a retroviral polymorphism.

Garth Nicholson of the University of Sydney, Australia, authored the 2007 paper identifying the 7q34-36 MND locus, and he was skeptical of the retroviral connection. “Our locus causes a non-lethal but disabling motor neuron disease,” he wrote in an e-mail to ARF. “It would need to be a functional gene (rather than a virus relic) and have a disease-specific mutation to be relevant to our disorder.” Further, Nicholson cautioned, “Every now and again retroviruses have been said to cause neurological disorders, but they have not stood the test of time.” Most recently, researchers hypothesize a link between Herpes viruses and Alzheimer’s disease (Porcellini et al., 2010; for review, see also Itzhaki and Wozniak, 2010).

Jeremy Garson of University College London, U.K., has studied RT expression in ALS serum (Andrews et al., 2000; Steele et al., 2005; McCormick et al., 2008). He said this is the first study to identify a specific retrovirus, but agreed the results are very preliminary. “If the findings are independently confirmed and extended by others, it is possible that HERV-K expression might in future become a useful biomarker or diagnostic/prognostic indicator (assuming, of course, that brain biopsy is not required to measure it),” he mused in an e-mail to ARF. “Aberrant HERV-K expression might prove important in understanding the pathogenesis of ALS,” he wrote.

Nath noted that drug companies already possess libraries of retroviral drugs originally developed for HIV. If, indeed, HERV-K or another retrovirus proves important in ALS, it might be worth testing on endogenous retroviruses, he suggested.—Amber Dance

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References

News Citations

1. ALS-like Symptoms in HIV-infected Patients Reversed by Retroviral Therapies 22 Nov 2002

Paper Citations

1. Ou SH, Wu F, Harrich D, García-Martínez LF, Gaynor RB. Cloning and characterization of a novel cellular protein, TDP-43, that binds to human immunodeficiency virus type 1 TAR DNA sequence motifs. J Virol. 1995 Jun;69(6):3584-96. PubMed.
3. McCormick AL, Brown RH Jr, Cudkowicz ME, Al-Chalabi A, Garson JA. Quantification of reverse transcriptase in ALS and elimination of a novel retroviral candidate. Neurology. 2008 Jan 22;70(4):278-83. PubMed.
4. MacGowan DJ, Scelsa SN, Waldron M. An ALS-like syndrome with new HIV infection and complete response to antiretroviral therapy. Neurology. 2001 Sep 25;57(6):1094-7. PubMed.
5. Moulignier A, Moulonguet A, Pialoux G, Rozenbaum W. Reversible ALS-like disorder in HIV infection. Neurology. 2001 Sep 25;57(6):995-1001. PubMed.
6. Verma A, Berger JR. ALS syndrome in patients with HIV-1 infection. J Neurol Sci. 2006 Jan 15;240(1-2):59-64. PubMed.
7. Bannert N, Kurth R. The evolutionary dynamics of human endogenous retroviral families. Annu Rev Genomics Hum Genet. 2006;7:149-73. PubMed.
8. Dolei A, Perron H. The multiple sclerosis-associated retrovirus and its HERV-W endogenous family: a biological interface between virology, genetics, and immunology in human physiology and disease. J Neurovirol. 2009 Jan;15(1):4-13. PubMed.
9. Perron H, Lang A. The human endogenous retrovirus link between genes and environment in multiple sclerosis and in multifactorial diseases associating neuroinflammation. Clin Rev Allergy Immunol. 2010 Aug;39(1):51-61. PubMed.
10. Gopinath S, Blair IP, Kennerson ML, Durnall JC, Nicholson GA. A novel locus for distal motor neuron degeneration maps to chromosome 7q34-q36. Hum Genet. 2007 Jun;121(5):559-64. PubMed.
11. Porcellini E, Carbone I, Ianni M, Licastro F. Alzheimer's disease gene signature says: beware of brain viral infections. Immun Ageing. 2010;7:16. PubMed.
12. Itzhaki RF, Wozniak MA. Alzheimer's disease and infection: Do infectious agents contribute to progression of Alzheimer's disease?. Alzheimers Dement. 2010 Jan;6(1):83-4; author reply 85. PubMed.
13. Andrews WD, Tuke PW, Al-Chalabi A, Gaudin P, Ijaz S, Parton MJ, Garson JA. Detection of reverse transcriptase activity in the serum of patients with motor neurone disease. J Med Virol. 2000 Aug;61(4):527-32. PubMed.
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Further Reading

Papers

1. Moyes D, Griffiths DJ, Venables PJ. Insertional polymorphisms: a new lease of life for endogenous retroviruses in human disease. Trends Genet. 2007 Jul;23(7):326-33. PubMed.
2. Johnston JB, Silva C, Holden J, Warren KG, Clark AW, Power C. Monocyte activation and differentiation augment human endogenous retrovirus expression: implications for inflammatory brain diseases. Ann Neurol. 2001 Oct;50(4):434-42. PubMed.
3. Matsuzaki T, Nakagawa M, Nagai M, Nobuhara Y, Usuku K, Higuchi I, Takahashi K, Moritoyo T, Arimura K, Izumo S, Akiba S, Osame M. HTLV-I-associated myelopathy (HAM)/tropical spastic paraparesis (TSP) with amyotrophic lateral sclerosis-like manifestations. J Neurovirol. 2000 Dec;6(6):544-8. PubMed.
4. Jolicoeur P. Neuronal loss in a lower motor neuron disease induced by a murine retrovirus. Can J Neurol Sci. 1991 Aug;18(3 Suppl):411-3. PubMed.
5. Berger JR, Espinosa PS, Kissel J. Brachial amyotrophic diplegia in a patient with human immunodeficiency virus infection: widening the spectrum of motor neuron diseases occurring with the human immunodeficiency virus. Arch Neurol. 2005 May;62(5):817-23. PubMed.
6. Langbaum JB, Chen K, Lee W, Reschke C, Bandy D, Fleisher AS, Alexander GE, Foster NL, Weiner MW, Koeppe RA, Jagust WJ, Reiman EM, . Categorical and correlational analyses of baseline fluorodeoxyglucose positron emission tomography images from the Alzheimer's Disease Neuroimaging Initiative (ADNI). Neuroimage. 2009 May 1;45(4):1107-16. PubMed.

News

1. San Diego: TDP-43 Targets Loom Large—But Where’s the Bull’s Eye? 25 Nov 2010
2. Québec: Teasing Out the Function of TDP-43 4 Oct 2010
3. ALS GWAS Confirm Chromosome 9 Risk Factor—But What Is It? 5 Sep 2010
4. Toxic TDP-43 Too Tough to Degrade, Plays Prion? 16 Jul 2010
5. New Gene for ALS: RNA Regulation May Be Common Culprit 27 Feb 2009
6. Genomewide Screen for SNPs Linked to Sporadic ALS Finds…Nothing Yet 14 Feb 2009
7. Gene Mutations Place TDP-43 on Front Burner of ALS Research 29 Feb 2008
8. ALS-like Symptoms in HIV-infected Patients Reversed by Retroviral Therapies 22 Nov 2002