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, have been implicated in atypical Parkinsonism. SJ1 knock-in (SJ1-KIRQ) mice carrying a disease-linked mutation display neurological manifestations reminiscent of Parkinsonism. 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 increase in 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.
Competing Interest Statement
The authors have declared no competing interest.
Footnotes
Other authors’ emails:
Xin Yi Ng: xinyi.ng{at}duke-nus.edu.sg
Yumei Wu: yumei.wu{at}yale.edu
Youneng Lin: youneng.lin{at}duke-nus.edu.sg
Sidra Mohamed Yaqoob: sidra.yaqoob{at}u.duke.nus.edu
Lois E. Greene: greenel{at}nhlbi.nih.gov
Pietro De Camilli: pietro.decamilli{at}yale.edu
We have now used a new title: Mutations in Parkinsonism linked endocytic proteins synaptojanin1 and auxilin have synergistic effects on dopaminergic axonal pathology. We rearranged the figure orders and revised the text to refer fig numbers in order. We now use the expression Parkinsonism instead of PD throughout the text. We have now added extensive quantification analysis (new Fig. 1F, 2F, 3B, 4B, 4D, 6G, 7G) and new representative images (new Fig. 2E, 6E, 6F, 7A, 7C (see details below)). In addition, we have added the following new data in revised manuscript: a) HPLC based analysis of the total DA content in the striatum from 4 genotypes (new Fig. 6H). b) Stereological counting of TH+ DA neurons in 1 month old double mutant midbrain (new Suppl Fig. 5B). c) Neuropeptide Y (NPY) immunostaining (New Suppl Fig. 1C, D).
- ABBREVIATIONS
- AADC
- Aromatic l-amino acid decarboxylase
- AP2
- Adaptor protein complex 2
- CCVs
- Clathrin coated vesicles
- ChAT
- Choline acetyltransferase
- ChINs
- Cholinergic interneurons
- DA
- Dopamine
- DAergic
- Dopaminergic
- DAT
- Dopamine transporter
- GAK
- Cyclin G-associated kinase
- GFAP
- Glial fibrillary acidic protein
- GWAS
- Genome-wide association study
- H&E
- Hematoxylin and eosin
- Iba1
- Ionized calcium-binding adapter molecule 1
- KI
- Knock-in
- KO
- Knockout
- LOF
- Loss-of-function
- MSNs
- Medium spiny neurons
- NPY
- Neuropeptide Y
- PD
- Parkinson’s Disease
- SJ1
- Synaptojanin 1
- SN
- Substantia nigra
- SVs
- Synaptic vesicles
- SV2
- Synaptic vesicle glycoprotein 2
- Syt1
- Synaptotagmin 1
- THINs
- TH-positive interneurons
- VTA
- Ventral tegmental area