Synj1 haploinsufficiency causes dopamine neuron vulnerability and alpha-synuclein accumulation in mice

Synaptojanin1 (synj1) is a phosphoinositide phosphatase with dual SAC1 and 5/-phosphatase enzymatic activities in regulating phospholipid signaling. The brain-enriched isoform has been shown to participate in synaptic vesicle (SV) recycling. More recently, recessive human mutations were identified in the two phosphatase domains of SYNJ1, including R258Q, R459P and R839C, which are linked to rare forms of early-onset Parkinsonism. We now demonstrate that Synj1 heterozygous deletion (Synj1^+/−), which is associated with an impaired 5/-phosphatase activity, also leads to Parkinson's disease (PD)-like pathologies in mice. We report that male Synj1^+/− mice display age-dependent motor function abnormalities as well as alpha-synuclein accumulation, impaired autophagy and dopaminergic terminal degeneration. Synj1^+/− mice contain elevated 5/-phosphatase substrate, PI(4,5)P₂, particularly in the midbrain neurons. Moreover, pharmacological elevation of membrane PI(4,5)P₂ in cultured neurons impairs SV endocytosis, specifically in midbrain neurons, and further exacerbates SV trafficking defects in Synj1^+/− midbrain neurons. We demonstrate down-regulation of SYNJ1 transcript in a subset of sporadic PD brains, implicating a potential role of Synj1 deficiency in the decline of dopaminergic function during aging.