Abnormal tRNA epigenetic modifications and related impact on neurodegenerative diseases.

Neurodegenerative diseases are a heterogeneous group of neurological disorders characterized by the progressive loss of neurons in the central or peripheral nervous system. Research on the pathogenesis and drug targets of these diseases still faces many challenges due to the complex etiology. In recent years, the role of transfer RNA (tRNA) epigenetic modifications in neurodegenerative diseases has attracted widespread attention. The tRNA modification is crucial for regulating codon recognition, maintaining molecular structural stability, and the generation of tRNA-derived fragments (tRFs). Recent studies have highlighted a close association between abnormal tRNA modifications and the pathogenesis of various neurodegenerative diseases; especially for abnormalities of elongator complex-dependent tRNA modification and methylation modification, which impact the translation process and tRFs levels. These changes regulate protein homeostasis and cellular stress responses, ultimately influencing the survival of neuronal cells. Moreover, significant changes in tRFs levels have been noted in neurodegenerative diseases, and special tRFs show distinct effects on neurodegenerative diseases. This review aims to provide an overview of the physiological functions of tRNA epigenetic modifications and their regulatory mechanisms in neurodegenerative diseases, covering both classical functions such as codon recognition and non-classical functions such as tRFs biogenesis. Additionally, the potential of targeting tRNA modifications for therapeutic applications is also discussed.