Abstract
Amitriptyline is a tricyclic antidepressant commonly prescribed for major depressive disorders, as well as depressive symptoms associated with various neurological disorders. A possible correlation between the use of tricyclic antidepressants and the occurrence of Parkinson’s disease has been reported, but its underlying mechanism remains unknown. The accumulation of misfolded protein aggregates has been suggested to cause cellular toxicity and has been implicated in the common pathogenesis of neurodegenerative diseases. Here, we examined the effect of amitriptyline on protein clearance and its relevant mechanisms in neuronal cells. Amitriptyline exacerbated the accumulation of abnormal aggregates in both in vitro neuronal cells and in vivo mice brain by interfering with the (1) formation of aggresome-like aggregates and (2) autophagy-mediated clearance of aggregates. Amitriptyline upregulated LC3B-II, but LC3B-II levels did not increase further in the presence of NH4Cl, which suggests that amitriptyline inhibited autophagic flux rather than autophagy induction. Amitriptyline interfered with the fusion of autophagosome and lysosome through the activation of PI3K/Akt/mTOR pathway and Beclin 1 acetylation, and regulated lysosome positioning by increasing the interaction between proteins Arl8, SKIP, and kinesin. To the best of our knowledge, we are the first to demonstrate that amitriptyline interferes with autophagic flux by regulating the autophagosome maturation during autophagy in neuronal cells. The present study could provide neurobiological clue for the possible correlation between the amitriptyline use and the risk of developing neurodegenerative diseases.
Highlights
Amitriptyline is a tricyclic antidepressant used to manage major depressive disorders, anxiety disorders, and other mental illnesses
In the present study, we showed that amitriptyline increases the accumulation of abnormal protein aggregates in neuronal cells and in the brain
Throughout our lives, our bodies are exposed to a variety of stress factors both externally and internally, which result in protein modifications and accumulation of misfolded proteins
Summary
Amitriptyline is a tricyclic antidepressant used to manage major depressive disorders, anxiety disorders, and other mental illnesses. Its chronic use has been demonstrated to be a risk factor for neurodegenerative diseases as evidenced by tricyclic antidepressants-induced increase in neuronal cell death in a dorsal root ganglion cell culture model[8], PD-related neurotoxicity and movement disorders caused by its longterm use in an in vivo model[9], and development of druginduced PD by antidepressants[10]. Despite these evidences, there is critical knowledge gap in understanding the underlying mechanism by which amitriptyline causes neurotoxicity
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