Synaptic endocytic failure drives dopamine deficiency and protein transfer-mediated striatal dopamine-like neuron compensation

Abstract

Presynaptic endocytic dysfunction is an early feature of Parkinson's disease (PD), but how dopamine circuits adapt to chronic synaptic failure remains unclear. In dopamine neuron-specific Synaptojanin 1 knockout mice, loss of this PD-linked endocytic protein causes terminal dystrophy and striatal dopamine deficiency, yet motor coordination is preserved. Chronic endocytic failure induces striatal dopamine-like neurons (DALNs) with circuit-dependent dopaminergic protein accumulation. DALNs do not arise through transcriptional reprogramming; instead, they acquire dopaminergic proteins from midbrain dopamine neurons through selective long-range transfer that favors soluble cargoes and can convey disease-associated proteins, including -synuclein and tau. Functionally, DALNs support local dopamine production, partially preserve motor performance and increase resistance to acute dopaminergic lesions. This adaptation is shared across PD-linked endocytic mutants and is developmentally constrained, but is not reproduced by acute denervation. Thus, synaptic endocytic stress triggers inter-neuronal protein transfer as an adaptive circuit mechanism supporting dopamine compensation and neuroprotection in early PD.