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A HML6 endogenous retrovirus on chromosome 3 is upregulated in amyotrophic lateral sclerosis motor cortex.

ABSTRACT: There is increasing evidence that endogenous retroviruses (ERVs) play a significant role in central nervous system diseases, including amyotrophic lateral sclerosis (ALS). Studies of ALS have consistently identified retroviral enzyme reverse transcriptase activity in patients. Evidence indicates that ERVs are the cause of reverse transcriptase activity in ALS, but it is currently unclear whether this is due to a specific ERV locus or a family of ERVs. We employed a combination of bioinformatic methods to identify whether specific ERVs or ERV families are associated with ALS. Using the largest post-mortem RNA-sequence datasets available we selectively identified ERVs that closely resembled full-length proviruses. In the discovery dataset there was one ERV locus (HML6_3p21.31c) that showed significant increased expression in post-mortem motor cortex tissue after multiple-testing correction. Using six replication post-mortem datasets we found HML6_3p21.31c was consistently upregulated in ALS in motor cortex and cerebellum tissue. In addition, HML6_3p21.31c showed significant co-expression with cytokine binding and genes involved in EBV, HTLV-1 and HIV type-1 infections. There were no significant differences in ERV family expression between ALS and controls. Our results support the hypothesis that specific ERV loci are involved in ALS pathology.

SUBMITTER: Jones AR

PROVIDER: S-EPMC8275748 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Background and purposeAmyotrophic lateral sclerosis is a progressive motor neuron disorder that involves degeneration of both upper and lower motor neurons. In patients with amyotrophic lateral sclerosis, pathologic studies and ex vivo high-resolution MR imaging at ultra-high field strength revealed the co-localization of iron and activated microglia distributed in the deep layers of the primary motor cortex. The aims of the study were to measure the cortical thickness and evaluate the distribution of iron-related signal changes in the primary motor cortex of patients with amyotrophic lateral sclerosis as possible in vivo biomarkers of upper motor neuron impairment.Materials and methodsTwenty-two patients with definite amyotrophic lateral sclerosis and 14 healthy subjects underwent a high-resolution 2D multiecho gradient-recalled sequence targeted on the primary motor cortex by using a 7T scanner. Image analysis consisted of the visual evaluation and quantitative measurement of signal intensity and cortical thickness of the primary motor cortex in patients and controls. Qualitative and quantitative MR imaging parameters were correlated with electrophysiologic and laboratory data and with clinical scores.ResultsUltra-high field MR imaging revealed atrophy and signal hypointensity in the deep layers of the primary motor cortex of patients with amyotrophic lateral sclerosis with a diagnostic accuracy of 71%. Signal hypointensity of the deep layers of the primary motor cortex correlated with upper motor neuron impairment (r = -0.47; P < .001) and with disease progression rate (r = -0.60; P = .009).ConclusionsThe combined high spatial resolution and sensitivity to paramagnetic substances of 7T MR imaging demonstrate in vivo signal changes of the cerebral motor cortex that resemble the distribution of activated microglia within the cortex of patients with amyotrophic lateral sclerosis. Cortical thinning and signal hypointensity of the deep layers of the primary motor cortex could constitute a marker of upper motor neuron impairment in patients with amyotrophic lateral sclerosis.

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A HML6 endogenous retrovirus on chromosome 3 is upregulated in amyotrophic lateral sclerosis motor cortex.

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