Parkinson’s-Linked Synaptojanin 1 Loss in Dopamine Neurons Triggers Synaptic Degeneration and Striatal TH Interneuron Compensation

Synaptic dysfunction is an early feature of Parkinson’s disease (PD). Synaptojanin 1 (SJ1), a phosphoinositide phosphatase linked to early-onset Parkinsonism (EOP), is essential for synaptic vesicle recycling. To elucidate SJ1’s specific role in dopamine (DA) neurons, we generated conditional SJ1 knockout (SJ1-DA cKO) mice. Complete loss of SJ1 resulted in severe, widespread dystrophy of striatal DA terminals, impaired DA metabolism and release, indicating SJ1 has a cell-autonomous role in synaptic transmission across midbrain DA subtypes. Under chronic DA deficiency, SJ1-DA cKO mice exhibited reduced basal locomotor activity but exaggerated amphetamine-induced hyperlocomotion, without obvious deficits in motor coordination. Notably, we observed robust emergence of striatal induced tyrosine hydroxylase-positive interneurons (iTHINs), which expressed multiple DA markers and formed connections with degenerating DA terminals, suggesting local adaptive plasticity. This developmental adaptive response was limited when SJ1 was acutely deleted in adult or aged DA neurons. Our findings highlight SJ1’s essential role in DA synapse maintenance and identify a compensatory mechanism that may inform future strategies for PD intervention.