Comprehensive review arguing that TAAR1 modulates dopamine, serotonin, and noradrenaline signaling via effects on transporters and VMAT2 and collates preclinical/clinical data positioning TAAR1 as a druggable target in neurodegeneration and psychiatric disease.

Highlights TAAR1 as a translationally actionable target to rebalance monoaminergic systems and potentially slow Parkinson's pathology, offering a clear therapeutic focus despite limited direct coverage of PD-specific mechanisms like alpha‑synuclein or mitochondrial dysfunction.

Trace amines (TAs) are typical biogenic amines which are found in the human body in pico-to-femto grams in the body fluids and tissues. TAs play crucial role in various physiological processes. Initially TAs were not considered significant due to their low levels in the body and no known receptor. After Trace amine-associated receptors (TAARs) discovery, TAs gained importance. TAs and TAARs are key regulators of neurotransmitter release thereby exerting their effects on dopaminergic, serotonergic, and noradrenergic pathways. This review delves into TAAR1, which is a G-protein coupled receptor which modulates neurotransmitter reuptake by regulating dopamine, serotonin, and noradrenaline transporters while also influencing vesicular monoamine transporter 2 function to ensure balanced neurotransmitter storage and release. Multiple studies have demonstrated that dysregulation of this system is closely linked to several neurodegenerative disorders, most notably Parkinson's disease and Alzheimer's disease. In addition, TAAR1 signaling has been strongly implicated in psychiatric conditions such as schizophrenia, mood disorders, and cognitive decline. These disorders share convergent pathological mechanisms, including oxidative stress, excitotoxicity, and neuroinflammation, all of which are influenced by TAAR1 activity. Growing preclinical and clinical evidence highlights TAARs, particularly TAAR1, as promising therapeutic targets for substance use disorders, due to their modulatory roles in dopaminergic and monoaminergic neurotransmission. Consequently, TAAR1 targeted pharmacological interventions present a promising approach for mitigating neurotransmitter imbalances and slowing neurodegenerative progression. This review seeks to provide a comprehensive understanding of the mechanistic and therapeutic implications of TAs and their receptors in various neurodegenerative conditions.