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Retroviruses and amyotrophic lateral sclerosis

Posted Apr 22 2011 12:00am

lou gehrig columbia Amyotrophic lateral sclerosis (ALS), also known as motor neuron disease or Lou Gehrig’s disease, is a fatal disorder of unknown etiology. The disease involves degeneration of motor neurons, leading to paralysis, respiratory failure, and death within five years. A viral etiology for ALS has been suggested but never proven. Retroviruses have been considered because they cause motor neuron disease in mice, and HIV-1 and HTLV-1 cause ALS-like symptoms in humans. Sera from some ALS patients have been shown to contain elevated levels of reverse transcriptase, an enzyme found in retrovirus particles. RNAs encoding this enzyme have now been found in the brains of ALS patients, and their origin appears to be the human endogenous retrovirus HERV-K.

Reverse transcriptase is a retroviral enzyme that makes a DNA copy of the viral RNA genome. It is present in the virion, a property that can be used to assay for reverse transcriptase activity. In one study of ALS patients, serum or cerebrospinal fluid is first centrifuged at low speeds to remove cells and debris. The cell-free extracts are then subjected to high speed centrifugation to pellet* viral particles. These are disrupted and an RNA template, a primer, and the precursors of DNA are added, and the mixture is incubated. A PCR reaction is then done; if any DNA has been made by reverse transcription, it will be amplified. In one study, 50% of ALS patients’ sera contained reverse transcriptase activity, at levels comparable to those found in AIDS patients. RT activity was detected in 7% of control sera.

What is the source of RT activity in sera from ALS patients? It does not appear to be from any known human exogenous retrovirus, including HIV-1, HIV-2, HTLV-1, HTLV-2, or HTLV-3. A recent study explored the possibility that the enzyme activity was due to the presence of the gammaretrovirus XMRV. However, the authors did not detect XMRV in DNA or RNA extracted from peripheral blood mononuclear cells of 20 ALS patients.

Human endogenous retroviruses are integrated into the human genome, but do not produce infectious virions and therefore are only transmitted through the germline. Although HERVs are highly mutated, some produce mRNA, viral proteins, and particles. At least 8% of the human genome consists of HERVs. One HERV, called HERV-K, may have integrated into the germline after the divergence of humans and chimpanzees.

The expression of HERV-K in ALS patients was examined in two ways: by PCR amplification of RNA extracted from brain tissues, using primers that amplify the pol gene (encoding RT), and by immunohistochemistry, using antibodies directed against the HERV-K reverse transcriptase protein. All samples used in the study were from patients who died of ALS (n=28), chronic systemic disease (n=10), accidental death (n=10) or Parkinson’s disease (n=12). HERV-K pol mRNA was detected in tissues from ALS patients and those who died of chronic systemic disease, but not from the accidental death or Parkinson’s patients. Levels of pol mRNA were highest in brains of ALS patients. Staining of brain sections with antibody to HERV-K pol revealed that the RT protein is produced only in neurons.

These observations raise a number of immediate questions. Is the RT activity detected in the serum of ALS patients from HERV-K? Why don’t all ALS patients have RT activity in their serum, and why is there such a wide range of HERV-K pol mRNA in the brain? Are the higher levels of HERV-K pol and RT observed in ALS patients a cause or a consequence of the disease? Answers to these questions will require more extensive epidemiological studies, and experiments to determine how HERV-K expression might lead to disease.

*pellet is jargon: the material at the bottom of a tube produced by centrifugation is a pellet, but scientists often use it as a verb, to indicate the separation of insoluble material by centrifugation.

[I used a photo of Lou Gehrig in a Columbia University uniform not only because I work at Columbia, but for several years I lived across the street from Gehrig's birthplace, on 94th street and First Avenue in New York City. On a building across the street from my apartment was a plaque with the inscription 'Lou Gehrig was born here'. I'd see it every day on my way to the lab. Years later, when I returned to look for the plaque, it had been stolen.]

McCormick AL, Brown RH Jr, Cudkowicz ME, Al-Chalabi A, & Garson JA (2008). Quantification of reverse transcriptase in ALS and elimination of a novel retroviral candidate. Neurology, 70 (4), 278-83 PMID: 18209202

Douville R, Liu J, Rothstein J, & Nath A (2011). Identification of active loci of a human endogenous retrovirus in neurons of patients with amyotrophic lateral sclerosis. Annals of neurology, 69 (1), 141-51 PMID: 21280084

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