Mutations in Parkinsonism-linked endocytic proteins synaptojanin1 and auxilin have synergistic effects on dopaminergic axonal pathology

Abstract

Parkinson's disease (PD) is a neurodegenerative disorder characterized by defective dopaminergic (DAergic) input to the striatum. Mutations in two genes encoding synaptically-enriched clathrin-uncoating factors, synaptojanin 1 (SJ1) and auxilin, result in PD. SJ1 knock-in (SJ1-KIRQ) mice carrying PD mutation display neurological manifestation reminiscent of PD. Here we report that auxilin knockout (Aux-KO) mice display dystrophic changes of a subset of nigrostriatal DAergic terminals similar to those of SJ1-KIRQ mice. Furthermore, Aux-KO/SJ1-KIRQ double mutant mice have shorter lifespan and more severe synaptic defects than single mutant mice. These include more numerous dystrophic striatal nerve terminals positive for DAergic markers and for the PD risk protein SV2C, as well as adaptive changes in striatal interneurons. The synergistic effect of the two mutations demonstrates a special lability of DAergic neurons to defects in clathrin uncoating, with implications for PD pathogenesis in at least some forms of this condition.

Parkinson mutations in DNAJC6 cause lipid defects and neurodegeneration that are rescued by Synj1

“…This is also supported by observations that Aux KO and Synj RQ mice show similar dystrophic neurons in relevant nigrostriatal pathways and that Synj1 RQ mice have increased levels of Auxilin (Cao et al, 2017;Vidyadhara et al, 2022;Yim et al, 2010) . Further data on BioRxiv, additionally suggests a synergistic relation between the two loss-of-function mutants: double mutants show more severe phenotypes; however, this work did not test if Synj expression rescues Aux mutant defects as we did here (Ng et al, 2022).…”

Impaired pre-synaptic plasticity and visual responses in auxilin-knockout mice

“… 13 , 14 , 15 Aux-KOs can be used to build a faithful model of DNAJC6 -linked PD in mice and Drosophila, recapitulating the cardinal features of nigrostriatal neuronal loss, alpha-synuclein pathology, and motor deficits. 16 , 17 , 18 As auxilin is broadly expressed in the brain and its endocytic function is universal to all synapses in the central nervous system, loss-of-auxilin is likely to impact the functions of brain regions beyond documented regions such as the hippocampus, dorsal striatum, and substantia nigra. 18 , 19 Because cognitive deficits are a common symptom of PD patients, including PARK19 patients, we utilized Aux-KO to explore the basis of these symptoms.…”