Haploinsufficiency of Parkinsonism Gene SYNJ1 Contributes to Dopamine neuron Vulnerability in Aged Mice

Parkinson’s disease (PD) is an age-dependent neurodegenerative disorder characterized by the loss of substantia nigra dopaminergic (DAergic) neurons in ventral midbrain (MB). Identification of interactions between aging and the known risk variants is crucial to understanding the etiology of PD. Recessive mutations in SYNJ1 have recently been linked to familial early-onset atypical Parkinsonism. We now show an age-dependent decline of SYNJ1 expression in the striatum as well as in striatal DAergic terminals of aged mice. Heterozygous deletion of SYNJ1 in mice causes selective elevation of PIP 2 in the MB, and manipulation of PIP 2 levels also impairs synaptic vesicle recycling preferentially in MB neurons. SYNJ1 +/- mice display progressive PD-like behavioral alterations and DAergic terminal degeneration. Furthermore, we found down-regulation of human SYNJ1 transcripts in a subset of sporadic PD brains, corroborating the role of an age-dependent decrease in SYNJ1 in predisposing DAergic neuron vulnerability and PD pathogenesis.