Telomerase gene therapy is an aspirational goal for a number of companies and research groups, and may presently be available via medical tourism in a limited, expensive, and probably not very efficient fashion. Groups such as Telocyte would like to run human trials of telomerase gene therapy for neurodegenerative conditions. Much of this is focused on the primary activity of telomerase, lengthening of telomeres and thus increased cell activity in older tissues. Telomerase, however, has other functions, not as well explored, that may still be relevant to aging and age-related disease. It may act to protect mitochondrial function in an environment of increased oxidative stress, for example. The paper here takes a look at what is know of these other mechanisms in the context of telomerase-based therapies for neurodegenerative disease.
Telomerase is an enzyme that in its canonical function extends and maintains telomeres, the ends of chromosomes. This reverse transcriptase function is mainly important for dividing cells that shorten their telomeres continuously. However, there are a number of telomere-independent functions known for the telomerase protein TERT (Telomerase Reverse Transcriptase). This includes the shuttling of the TERT protein from the nucleus to mitochondria where it decreases oxidative stress, apoptosis sensitivity, and DNA damage.
Recently, evidence has accumulated on a protective role of TERT in brain and postmitotic neurons. This function might be able to ameliorate the effects of toxic proteins such as amyloid-β, pathological tau and α-synuclein involved in neurodegenerative diseases such as Alzheimer's disease (AD) and Parkinson's disease (PD). However, the protective mechanisms of TERT are not clear yet. Recently, an activation of autophagy as an important protein degradation process for toxic neuronal proteins by TERT has been described.
This review summarises the current knowledge about the non-canonical role of the telomerase protein TERT in brain and shows its potential benefit for the amelioration of brain ageing and neurodegenerative diseases such as AD and PD. This might form the basis for the development of novel strategies and therapies against those diseases.