The Molecular Link Between TDP-43, Endogenous Retroviruses and Inflammatory Neurodegeneration in Amyotrophic Lateral Sclerosis: a Potential Target for Triumeq, an Antiretroviral Therapy

Megan Dubowsky, Frances Theunissen, Jillian M. Carr, Mary-Louise Rogers

Research output: Contribution to journalReview articlepeer-review

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Abstract


Amyotrophic lateral sclerosis (ALS), also known as motor neuron disease (MND), is a progressive neurological disorder, characterised by the death of upper and lower motor neurons. The aetiology of ALS remains unknown, and treatment options are limited. Endogenous retroviruses (ERVs), specifically human endogenous retrovirus type K (HERV-K), have been proposed to be involved in the propagation of neurodegeneration in ALS. ERVs are genomic remnants of ancient viral infection events, with most being inactive and not retaining the capacity to encode a fully infectious virus. However, some ERVs retain the ability to be activated and transcribed, and ERV transcripts have been found to be elevated within the brain tissue of MND patients. A hallmark of ALS pathology is altered localisation of the transactive response (TAR) DNA binding protein 43 kDa (TDP-43), which is normally found within the nucleus of neuronal and glial cells and is involved in RNA regulation. In ALS, TDP-43 aggregates within the cytoplasm and facilitates neurodegeneration. The involvement of ERVs in ALS pathology is thought to occur through TDP-43 and neuroinflammatory mediators. In this review, the proposed involvement of TDP-43, HERV-K and immune regulators on the onset and progression of ALS will be discussed. Furthermore, the evidence supporting a therapy based on targeting ERVs in ALS will be reviewed.
Original languageEnglish
Pages (from-to)6330-6345
Number of pages16
JournalMOLECULAR NEUROBIOLOGY
Volume60
Issue number11
Early online date14 Jul 2023
DOIs
Publication statusPublished - Nov 2023

Keywords

  • Amyotrophic lateral sclerosis
  • Motor neuron disease
  • TDP-43
  • Endogenous retrovirus
  • HERV-K neuroinfammation
  • Antiretroviral therapy
  • Triumeq

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