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Altered Striatal Dopamine Levels in Parkinson's Disease VPS35 D620N

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Altered Striatal Dopamine Levels in Parkinson's Disease VPS35 D620N Vanan et al. Mol Brain (2020) 13:164 https://doi.org/10.1186/s13041-020-00704-3 RESEARCH Open Access Altered striatal dopamine levels in Parkinson’s disease VPS35 D620N mutant transgenic aged mice Sarivin Vanan1† , Xiaoxia Zeng1†, Sook Yoong Chia1, Katarina Varnäs2, Mei Jiang1, Ke Zhang1, Wuan Ting Saw3, Parasuraman Padmanabhan4, Wei‑Ping Yu5,6, Zhi‑Dong Zhou3,7, Christer Halldin2,4, Balázs Gulyás2,4, Eng‑King Tan3,7,8* and Li Zeng1,7,9* Abstract Vacuolar protein sorting 35 (VPS35) is a major component of the retromer complex that mediates the retrograde transport of cargo proteins from endosomes to the trans‑Golgi network. Mutations such as D620N in the VPS35 gene have been identifed in patients with autosomal dominant Parkinson’s disease (PD). However, it remains poorly understood whether and how VPS35 defciency or mutation contributes to PD pathogenesis; specifcally, the studies that have examined VPS35 thus far have difered in results and methodologies. We generated a VPS35 D620N mouse model using a Rosa26‑based transgene expression platform to allow expression in a spatial manner, so as to better address these discrepancies. Here, aged (20‑months‑old) mice were frst subjected to behavioral tests. Subsequently, DAB staining analysis of substantia nigra (SN) dopaminergic neurons with the marker for tyrosine hydroxylase (TH) was performed. Next, HPLC was used to determine dopamine levels, along with levels of its two metabolites, 3,4‑dihy‑ droxyphenylacetic acid (DOPAC) and homovanillic acid (HVA), in the striatum. Western blotting was also performed to study the levels of key proteins associated with PD. Lastly, autoradiography (ARG) evaluation of [ 3H]FE‑PE2I binding to the striatal dopamine transporter DAT was carried out. We found that VPS35 D620N Tg mice displayed a signifcantly higher dopamine level than NTg counterparts. All results were then compared with that of current VPS35 studies to shed light on the disease pathogenesis. Our model allows future studies to explicitly control spatial expression of the transgene which would generate a more reliable PD phenotype. Keywords: Parkinson’s disease, VPS35 D620N, Striatal dopamine, Transgenic mice, Behavioral assay Background 80 years old and older [1]. Individuals with PD display Parkinson’s disease (PD) is one of the most common neu- motor symptoms such as resting tremor, bradykinesia, rodegenerative disorders globally, with the prevalence rigidity and postural instability [2]. Nonmotor symptoms of PD being reported to be approximately 1% in people may also be present, including cognitive impairment, 60 years old and older, and increasing to 1–3% in those mood disorders and difculty swallowing [3]. Although PD is largely an idiopathic disease, approximately 5 to 10% of cases are hereditary, with mutations in at least 13 *Correspondence: [email protected]; [email protected] genes being shown to cause familial PD; one of these is †Sarivin Vanan and Xiaoxia Zeng contributed equally to this work 1 Neural Stem Cell Research Lab, Research Department, National the vacuolar protein sorting 35 (VPS35, PARK17) gene Neuroscience Institute, Singapore 308433, Singapore [4, 5]. 3 Department of Research, National Neuroscience Institute, 11 Jalan Tan In previous exome sequencing studies, the D620N Tock Seng, Singapore 308433, Singapore Full list of author information is available at the end of the article mutation in VPS35 has been identifed as being © The Author(s) 2020. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creat iveco mmons .org/licen ses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creat iveco mmons .org/publi cdoma in/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data. Vanan et al. Mol Brain (2020) 13:164 Page 2 of 15 pathogenic for late-onset autosomal dominant PD in allowed us to study a mouse model in which there is spa- numerous families from various ethnic backgrounds [6, tial expression of the transgene in a physiologically rel- 7]. Te VPS35 gene encodes a key component of the ret- evant manner, which would generate a more reliable PD romer complex, which operates by packaging particular phenotype. Furthermore, we analyzed mice at an even endosomal cargoes into tubules and vesicles and then older age (20-months-old) to reveal age-related neurode- transporting these cargoes either to the trans-Golgi net- generation in Parkinson’s disease. work or to the plasma membrane [8]. Te retromer con- sists of two subprotein complexes: the cargo-selective Results complex, which contains a VPS35-VPS29-VPS26 trimer Generation of VPS35 D620N transgenic mice [9], and the membrane deformation complex, which con- Te generation of this VPS35 D620N mouse model sists of a sorting nexin dimer [10]. started with the microinjection of the entire VPS35- Te upregulation of wild-type (WT) human VPS35 D620N construct into pronuclei fertilized oocytes of has been shown to rescue α-synuclein-induced neu- pseudopregnant C57BL/6j females. After establish- rodegeneration, and the knockdown of endogenous ing germ-line transmission, two founder lines were VPS35 resulted in substantial neuronal loss in the hip- then backcrossed to produce homozygous founders pocampus of α-synuclein transgenic (Tg) mice. Tese (C57BL/6J-LSL-VPS35 D620N/D620N). Te VPS35-D620N fndings suggest that VPS35 is able to functionally antag- construct itself was inserted into the mouse Rosa26 locus onize α-synuclein-mediated neurodegeneration [11]. under the control of an exogenous CAGGS promoter Tis result is also supported by the fndings of Linhart’s (rather than the endogenous Rosa26 promoter). A strong study, in which they determined that the overexpression transcriptional termination signal sequence fanked by of VPS35 signifcantly protects against locomotor defcits two loxP sites was inserted between the promoter and observed in mutant LRRK2 fies, while knocking down the transgene coding sequence, which is, in turn, directly the expression of VPS35 in dopaminergic neurons causes adjacent to a HA tag sequence (Fig. 1A). Under these signifcant locomotor impairment [12]. Together, these circumstances (i.e., in the absence of Cre recombinase), fndings indicate that VPS35 plays a protective role in the transgene coding sequence is not expressed due to regard to dopamine neurons. However, other studies have the presence of the transcriptional termination signal also presented evidence that VPS35 can have an adverse sequence. However, in the presence of Cre recombi- efect. In rat primary cortical cultures, the overexpression nase, the transcriptional termination signal sequence is of human WT or VPS35 D620N induces neuronal cell excised, which leads to the derepression of the transgene. death, while in a novel viral-mediated gene transfer rat Since the homozygous founder line (C57BL/6J-LSL- model, the expression of human WT or VPS35 D620N VPS35D620N/D620N) bearing the VPS35 D620N allele can induces substantial degeneration and axonal pathology in only be expressed in the brain after Cre-mediated exci- substantia nigra (SN) dopaminergic neurons [13]. sion of the STOP cassette, the homozygous founder lines Hence, the generation of genetically engineered rodent were crossed with C57BL/6J mice (National University of models with the VPS35 D620 mutation could not only Singapore Comparative Medicine Centre) frst to obtain overcome the problems inherent in using viral transfec- hemizygous mice (C57BL/6J-LSL-VPS35D620N/−). Sub- tion but could also provide a crucial tool for understand- sequently, these hemizygous mice were crossed with the ing the pathophysiology of VPS35. Ishizu’s group frst B6.Cg-Tg(Nes-cre)1kln/J mouse strain purchased from investigated the VPS35 D620N gene in vivo using D620N Jackson Laboratories [15]. Te VPS35 D620N transgene knock-in (KI) mice, and they found neither homozy- can now be specifcally expressed in the central and gous nor heterozygous VPS35 D620N KI mice had suf- peripheral nervous systems. More importantly, this fered premature death or had developed clear signs of allows transgenic expression in brain tissue. To confrm neurodegeneration at up to 15 months of age [14]. Tese the success of the transgene sequence insertion, PCR results suggest that the VPS35 D620N allele is still func- amplifcation was performed using designated primers, tional and does not cause obvious dopamine neuron loss; followed by electrophoresis on a 2% (w/v) agarose gel. All they also suggest that the VPS35 D620N allele is a par- VPS35 D620N transgenic mice showed a clear band at tial loss-of-function allele, and genetic predisposition and 525 bp, while nontransgenic (NTg) mice had no band. All age-related alterations in the nigrostriatal dopamine sys- mice used in this study (both VPS35 D620N NTg and Tg) tem cooperatively infuence the pathogenesis of VPS35. were Nestin cre positive (Fig. 1b). Here, we generated a novel VPS35 D620N transgenic mouse line by integrating a single copy of a transgene Characterization of transgenic VPS35 D620N mice (VPS35-D620N) into the mouse Rosa26 locus under the Given that VPS35 D620N mice were crossed with Nes- control of an exogenous CAGGS promoter. Tis strategy tin cre mice, VPS35 D620N (detected by HA antibody) Vanan et al. Mol Brain (2020) 13:164 Page 3 of 15 Fig.
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