Diseases of the nERVous system: retrotransposon activity in neurodegenerative disease

Abstract

Transposable Elements (TEs) are mobile genetic elements whose sequences constitute nearly half of the human genome. Each TE copy can be present in hundreds to thousands of locations within the genome, complicating the genetic and genomic studies of these highly repetitive sequences. The recent development of better tools for evaluating TE derived sequences in genomic studies has enabled an increasing appreciation for the contribution of TEs to human development and disease. While some TEs have contributed novel and beneficial host functions, this review will summarize the evidence for detrimental TE activity in neurodegenerative disorders. Much of the evidence for pathogenicity implicates endogenous retroviruses (ERVs), a subset of TEs that entered the genome by retroviral infections of germline cells in our evolutionary ancestors and have since been passed down as a substantial fraction of the human genome. Human specific ERVs (HERVs) represent some of the youngest ERVs in the genome, and thus are presumed to retain greater function and resultant pathogenic potential.

Keywords: Aicardi-Goutieres syndrome; Alzheimer’s disease; Amyotrophic lateral sclerosis; Endogenous retroviruses; Multiple sclerosis; Neurodegenerative disease; Transposable elements.

Fig. 1

Transposable element (TE) activity in four neurological disorders: Aicardi-Goutieres Syndrome (AGS), Multiple Sclerosis (MS), Amyotrophic Lateral Sclerosis (ALS), and Alzheimer’s Disease (AD). In AGS and MS, TE nucleic acids and endogenous retroviral (ERV) proteins may be driving inflammation through innate immune sensing pathways. In ALS and AD, the pathogenic effects of TEs appear more localized to either motor neurons (in ALS), and hippocampal or cortical neurons (in AD). Innate immune pathways are activated by double-stranded RNAs and cDNAs produced by TE/ERV transcription and reverse transcription, respectively; this is the primary mechanism implicated in AGS, and could be at play in the other disorders. In addition, envelope proteins from the HERVW and HERVK class have been shown to be neurotoxic when expressed, and implicated in MS and ALS, respectively. Increased mobilization of fully competent TEs has not been convincingly demonstrated for any neurodegenerative disorder, though this mechanism has not been fully tested