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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)P 2 , particularly in the midbrain neurons. Moreover, pharmacological elevation of membrane PI(4,5)P 2  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.

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