Identification of novel ATP13A2 interactors and their role in -synuclein misfolding and toxicity

Department of Neurology, Massachusetts General Hospital, Harvard Medical School, MassGeneral Institute for Neurodegenerative Disease, Charlestown, MA 02129, USA.
Human Molecular Genetics (Impact Factor: 6.39). 05/2012; 21(17):3785-94. DOI: 10.1093/hmg/dds206
Source: PubMed

ABSTRACT Lysosomes are responsible for degradation and recycling of bulky cell material, including accumulated misfolded proteins and dysfunctional organelles. Increasing evidence implicates lysosomal dysfunction in several neurodegenerative disorders, including Parkinson's disease and related synucleinopathies, which are characterized by the accumulation of α-synuclein (α-syn) in Lewy bodies. Studies of lysosomal proteins linked to neurodegenerative disorders present an opportunity to uncover specific molecular mechanisms and pathways that contribute to neurodegeneration. Loss-of-function mutations in a lysosomal protein, ATP13A2 (PARK9), cause Kufor-Rakeb syndrome that is characterized by early-onset parkinsonism, pyramidal degeneration and dementia. While loss of ATP13A2 function plays a role in α-syn misfolding and toxicity, the normal function of ATP13A2 in the brain remains largely unknown. Here, we performed a screen to identify ATP13A2 interacting partners, as a first step toward elucidating its function. Utilizing a split-ubiquitin membrane yeast two-hybrid system that was developed to identify interacting partners of full-length integral membrane proteins, we identified 43 novel interactors that primarily implicate ATP13A2 in cellular processes such as endoplasmic reticulum (ER) translocation, ER-to-Golgi trafficking and vesicular transport and fusion. We showed that a subset of these interactors modified α-syn aggregation and α-syn-mediated degeneration of dopaminergic neurons in Caenorhabditis elegans, further suggesting that ATP13A2 and α-syn are functionally linked in neurodegeneration. These results implicate ATP13A2 in vesicular trafficking and provide a platform for further studies of ATP13A2 in neurodegeneration.

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Available from: Guy A Caldwell, Sep 27, 2015
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    • "PINK1, parkin, and HTRA2 are all proteins that regulate mitochondrial function, possibly including mitophagy (Plun-Favreau et al., 2007; Narendra et al., 2010). ATP13A2 and GBA are both associated with lysosomes (Mazzulli et al., 2011; Usenovic et al., 2012). The consistent appearance of vesicular biology in the pathophysiology of PD suggests that interactions of LRRK2 with vesicles are likely to contribute to its mechanism of disease pathogenesis. "
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    ABSTRACT: LRRK2 is a protein that interacts with a plethora of signaling molecules, but the complexity of LRRK2 function presents a challenge for understanding the role of LRRK2 in the pathophysiology of Parkinson's disease (PD). Studies of LRRK2 using over-expression in transgenic mice have been disappointing, however, studies using invertebrate systems have yielded a much clearer picture, with clear effects of LRRK2 expression, knockdown or deletion in Caenorhabditis elegans and Drosophila on modulation of survival of dopaminergic neurons. Recent studies have begun to focus attention on particular signaling cascades that are a target of LRRK2 function. LRRK2 interacts with members of the mitogen activated protein kinase (MAPK) pathway and might regulate the pathway action by acting as a scaffold that directs the location of MAPK pathway activity, without strongly affecting the amount of MAPK pathway activity. Binding to GTPases, GTPase-activating proteins and GTPase exchange factors are another strong theme in LRRK2 biology, with LRRK2 binding to rac1, cdc42, rab5, rab7L1, endoA, RGS2, ArfGAP1, and ArhGEF7. All of these molecules appear to feed into a function output for LRRK2 that modulates cytoskeletal outgrowth and vesicular dynamics, including autophagy. These functions likely impact modulation of α-synuclein aggregation and associated toxicity eliciting the disease processes that we term PD.
    Frontiers in Molecular Neuroscience 07/2014; 7:64. DOI:10.3389/fnmol.2014.00064 · 4.08 Impact Factor
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    • "dat-1::human α-synuclein No obvious defect Failure in modulation of locomotory rate in response to food (Kuwahara et al., 2006). dat-1::human α-synuclein No obvious defect ATP13A2 modified α-synuclein aggregation and toxicity to dopamine neurons (Usenovic et al., 2012). unc-51::human α-synuclein No obvious motor deterioration α-synuclein may destroy endocytosis pathway and the dysfunction becomes severe when endocytic machineries are defective (Kuwahara et al., 2008). "
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    ABSTRACT: Neurodegenerative diseases which include Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), Huntington disease (HD), and others are becoming an increasing threat to human health worldwide. The degeneration and death of certain specific groups of neurons is the hallmark of these diseases. Despite the research progress in identification of several disease-related genes, the mechanisms underlying the neurodegeneration in these diseases remain unclear. Given the molecular conservation in neuronal signaling between Caenorhabditis elegans and vertebrates, increasing number of research scientists has used the nematode to study this group of diseases. This review paper will focus on the model system that has been established in Caenorhabditis elegans to investigate the pathogenetic roles of those reported disease-related genes in AD, PD, ALS, HD and others. The progress in Caenorhabditis elegans provides useful information of the genetic interactions and molecular pathways that are critical in the disease process, and may help our better understanding of the disease mechanisms and search for new therapeutics for these devastating diseases.
    Experimental Neurology 10/2013; 250. DOI:10.1016/j.expneurol.2013.09.024 · 4.70 Impact Factor
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    • "Please cite this article in press as: Fu, R.-H., et al., Acetylcorynoline attenuates dopaminergic neuron degeneration and a-synuclein aggregation in animal models of Parkinson's disease, Neuropharmacology (2013), genes of PD in previous studies (Hamamichi et al., 2008; Harrington et al., 2011; Jadiya and Nazir, 2012; Kamp et al., 2010; Karpinar et al., 2009; Kaur et al., 2012; Roodveldt et al., 2009; Shukla et al., 2012; Usenovic et al., 2012). Third, the expression and subsequent aggregation of a-synuclein in the muscle lead to PD-like progressive decline of motility in C. elegans, demonstrating the in vivo toxicity of these aggregates (Bodhicharla et al., 2012; van der Goot et al., 2012; van Ham et al., 2010). "
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    ABSTRACT: Parkinson's disease (PD), the second most common neurodegenerative disease, impairs motor skills and cognitive function. To date, the drugs used for PD treatment provide only symptomatic relief. The identification of new drugs that show benefit in slowing the decline seen in PD patients is the focus of much current research. Acetylcorynoline is the major alkaloid component derived from Corydalis bungeana, a traditional Chinese medical herb. It has been shown to have anti-inflammatory properties, but no studies have yet described the effects of acetylcorynoline on PD. The aim of this study was to evaluate the potential for acetylcorynoline to improve PD in C. elegans models. In the present study, we used a pharmacological strain (BZ555) that expresses green fluorescent protein specifically in dopaminergic neurons, and a transgenic strain (OW13) that expresses human α-synuclein in muscle cells to study the antiparkinsonian effects of acetylcorynoline. Our experimental data showed that treatment with up to 10 mM acetylcorynoline does not cause toxicity in animals. Acetylcorynoline significantly decreases dopaminergic neuron degeneration induced by 6-hydroxydopamine in BZ555 strain; prevents α-synuclein aggregation; recovers lipid content in OW13 strain; restores food-sensing behavior, and dopamine levels; and prolongs life-span in 6-hydroxydopamine-treated N2 strain, thus showing its potential as a possible antiparkinsonian drug. Acetylcorynoline may exert its effects by decreasing egl-1 expression to suppress apoptosis pathways and by increasing rpn5 expression to enhance the activity of proteasomes.
    Neuropharmacology 08/2013; 82. DOI:10.1016/j.neuropharm.2013.08.007 · 5.11 Impact Factor
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