Telomere shortening in neurological disorders: an abundance of unanswered questions

Abstract

Telomeres, ribonucleoprotein complexes that cap eukaryotic chromosomes, typically shorten in leukocytes with aging. Aging is a primary risk factor for neurodegenerative disease (ND), and a common assumption has arisen that leukocyte telomere length (LTL) can serve as a predictor of neurological disease. However, the evidence for shorter LTL in Alzheimer's and Parkinson's patients is inconsistent. The diverse causes of telomere shortening may explain variability in LTL between studies and individuals. Additional research is needed to determine whether neuronal and glial telomeres shorten during aging and in neurodegenerative disorders, if and how LTL is related to brain cell telomere shortening, and whether telomere shortening plays a causal role in or exacerbates neurological disorders.

Figure 1

Causes of telomere shortening. Telomerase is a reverse transcriptase that can maintain telomere length by adding the TTAGGG sequence to the telomere. High levels of telomerase are present in stem cells and may contribute to their ‘immortal’ phenotype. A reduction in telomerase expression contributes to telomere shortening in mitotic cells. Telomere trimming occurs in dividing cells and involves homologous recombination-mediated removal of telomere loops. Inflammation can accelerate telomere shortening by enhancing cell proliferation and by causing oxidative damage to telomere-associated proteins and telomeric DNA. As a consequence of telomere shortening, cells may undergo senescence or apoptosis.

Figure 2

Impact of telomere length and telomerase activity on hematopoietic stem cells (HSC; panel A) and neural stem cells (NSC; panel B), and their progeny, in the context of Alzheimer’s disease (AD) and Parkinson’s disease (PD). Telomere length- purple, upper left quadrant; telomerase activity- red up, upper right quadrant; AD- blue, lower left quadrant; PD- green, lower right quadrant. +, increase; −, decrease; ?, unknown; CLP, common lymphocyte progenitor; CMP, common monocyte progenitor; GPC, glial progenitor cell; mNK, mature natural killer cell; NK, natural killer; NPC, neuron progenitor cell; NSC, neural stem cell.