Pathological forms of TDP-43 in amyotrophic lateral sclerosis (ALS) promote aberrant telomere elongation

Biochim Biophys Acta Mol Basis Dis. 2025 May 14;1871(7):167906. doi: 10.1016/j.bbadis.2025.167906. Online ahead of print.

Abstract

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder affecting motor neurons. TAR DNA-binding protein 43 (TDP-43) mis-localisation from the nucleus to the cytoplasm is the major pathological characteristic of ALS. Telomeres are repetitive DNA sequences found in complex with proteins at chromosomal ends. The shelterin protein complex protects telomeres from DNA damage by producing characteristic t-loop structures, and telomere repeat binding factor 2 (TRF2) has an essential role in this process. Telomere dysregulation is reported in ALS, but conflicting findings have been obtained. Here we examined if telomere dysregulation is present in cortical neurons in a mouse model with pathological mis-localisation of TDP-43 to the cytoplasm - TDP-43 rNLS - compared to controls, and in cortical primary neurons expressing TDP-43 ALS associated mutations (A315T, A90V). We demonstrate that telomeres are significantly longer and of more variable in length in the TDP-43 rNLS model compared to controls. This was proceeded by downregulation of TRF2 in early disease stages with subsequent upregulation of TRF2 at advanced disease in TDP-43 rNLS mice. Longer telomeres were also present in primary cortical neurons expressing mutant TDP-43. A trend towards TRF2 upregulation was also present in human ALS spinal cord lysates. We detected dysregulation of catalytic subunit of telomerase, TERT, and a trend towards upregulation of telomere interacting protein, Rif 1 in these mice and human ALS spinal cord lysates. The longer telomeres were independent of the alternative lengthening of telomeres (ALT) mechanism of maintaining telomere length. Similarly, no DNA damage at telomere sites was detected. Our findings imply that telomere protection is compromised in ALS, leading to longer telomeres in neurons in ALS associated with TDP-43 pathology.

Keywords: ALS; DNA damage; Neurodegeneration; TDP-43 pathology; Telomere dysfunction; Telomeres.