Altered dopamine release and monoamine transporters in Vps35 p.D620N knock-in mice

Cataldi, Stefano; Follett, Jordan; Fox, Jesse; Tatarnikov, Igor; Kadgien, Chelsie; Khinda, Jaskaran; Milnerwood, Austen J.; Farrer, Matthew J.

doi:10.1038/s41531-018-0063-3

Cited by 65 publications

(91 citation statements)

References 41 publications

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“…4). These results are contradictory to the studies that found no signi cant difference in DA levels between VPS35 D620N KI mice and controls (14, 21) However, the lack of any signi cant difference in DOPAC and HVA levels are consistent throughout these studies (14,21) and ours ( Table 1). We speculate that the mutated form of VPS35 protein is still functional to a certain degree in vivo, which is supported by Ishizu's results (14).…”

Section: Discussioncontrasting

confidence: 99%

Altered Striatal Dopamine Levels in Parkinson’s Disease VPS35 D620N Mutant Transgenic Aged Mice

Vanan

Zeng

Chia

et al. 2020

Preprint

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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 identified in patients with autosomal dominant Parkinson’s disease (PD). However, it remains poorly understood whether and how VPS35 deficiency or mutation contributes to PD pathogenesis; specifically, the studies that have examined VPS35 thus far have differed 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 first 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-dihydroxyphenylacetic 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 significantly 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.

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Section: Discussioncontrasting

confidence: 99%

Altered Striatal Dopamine Levels in Parkinson’s Disease VPS35 D620N Mutant Transgenic Aged Mice

Vanan

Zeng

Chia

et al. 2020

Preprint

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“…Such specificity could explain the late onset and could account for anatomical and cell type specificity of the disease, although earlier changes conferred by VPS35 mutation have been described. For example, a recent study has shown that VPS35‐D620N knockin mice display altered striatal dopamine release and turnover by 3 months of age (Cataldi et al, ). Specificity may also be driven by the more restricted localization of LRRK2.…”

Section: Three Park Gene Groups In Space and Timementioning

confidence: 99%

Are we listening to everything the PARK genes are telling us?

Benson

Huntley

2019

J of Comparative Neurology

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The cardinal motor symptoms that define Parkinson's disease (PD) clinically have been recognized for over 200 years. That these symptoms arise following the loss of dopamine neurons in the substantia nigra has been known for the last 50. These long-established facts have fueled a broadly held expectation that degenerating dopaminergic neurons alone hold the key to understanding and curing PD. This prevalent expectation is at odds with the observation that many nonmotor symptoms, including depression and cognitive inflexibility among others, can appear years earlier than the overt dopaminergic neuron degeneration that drives motor abnormalities and are not improved by levodopa treatment. Thus, preserving or rescuing dopamine neuron health and function is of paramount importance, but this alone fails to capture the underlying neurobiology of earlier-appearing nonmotor symptoms. Insight into the complete landscape of disease-related abnormalities and the context in which they arise can be gleaned from a more comprehensive consideration of the PARK genes that are known to cause PD. Here, we make the case that a full incorporation of research showing when and where PARK genes are expressed as well as the impact of gene mutation on function throughout life, in tandem with research studying how dopaminergic neuron degeneration begins, is essential for a full understanding of the multi-dimensional etiology of PD. A broad view may also reveal something about long-term adjustments cells and systems make in response to gene mutation and help to identify mechanisms conferring the resilience or susceptibility of some cells and systems over others. K E Y W O R D Scritical periods, development, nonmotor symptoms, PARK genes, Parkinson's disease, protein degradation, protein trafficking

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“…It is also important to recognize that EMTP genes may encode proteins involved in more than one aspect of endosomal biology and in specialized cell types . Mutations in LRRK2 , SNCA, VPS35 and DNAJC13 , linked to late‐onset parkinsonism that most closely resembles idiopathic PD, may subtly impair synaptic/early endosomal processes as well as endosomal autophagy . Although molecular mechanisms of dopaminergic axonal arbor degeneration may be separate and distinct from those of neuronal soma, many of these protein components appear to be important in both …”

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confidence: 99%