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Neuronal ceroid lipofuscinosis protein CLN3 interacts with motor proteins and modifies location of late endosomal compartments

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Abstract

CLN3 is an endosomal/lysosomal transmembrane protein mutated in classical juvenile onset neuronal ceroid lipofuscinosis, a fatal inherited neurodegenerative lysosomal storage disorder. The function of CLN3 in endosomal/lysosomal events has remained elusive due to poor understanding of its interactions in these compartments. It has previously been shown that the localisation of late endosomal/lysosomal compartments is disturbed in cells expressing the most common disease-associated CLN3 mutant, CLN3∆ex7-8 (c.462-677del). We report here that a protracted disease causing mutant, CLN3E295K, affects the properties of late endocytic compartments, since over-expression of the CLN3E295K mutant protein in HeLa cells induced relocalisation of Rab7 and a perinuclear clustering of late endosomes/lysosomes. In addition to the previously reported disturbances in the endocytic pathway, we now show that the anterograde transport of late endosomal/lysosomal compartments is affected in CLN3 deficiency. CLN3 interacted with motor components driving both plus and minus end microtubular trafficking: tubulin, dynactin, dynein and kinesin-2. Most importantly, CLN3 was found to interact directly with active, guanosine-5′-triphosphate (GTP)-bound Rab7 and with the Rab7-interacting lysosomal protein (RILP) that anchors the dynein motor. The data presented in this study provide novel insights into the role of CLN3 in late endosomal/lysosomal membrane transport.

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Abbreviations

ER:

Endoplasmic reticulum

GST:

Glutathione S-transferase

GTP:

Guanosine-5′-triphosphate

LAMP-1:

Lysosomal-associated membrane protein 1

RILP:

Rab7-interacting lysosomal protein

SBDS:

Shwachmann-Bodian-Diamond syndrome protein

siRNA:

Small interfering RNA

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Acknowledgments

Auli Toivola, Seija Puomilahti, Anne Nyberg, and Kathrin Oelgeschläger are thanked for excellent technical assistance. We thank the Biomedicum Imaging Unit (Biomedicum, Helsinki, Finland) for providing the facilities for the image analysis. This work was supported by the Academy of Finland, Centre of Excellence in Complex Disease Genetics [129680], the Sigrid Juselius Foundation, Rinnekoti Research Foundation/Brain Foundation of Finland and the Finnish Cultural Foundation.

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Authors and Affiliations

  1. National Institute for Health and Welfare and FIMM, Institute for Molecular Medicine Finland, Biomedicum Helsinki, PO Box 104, 00251, Helsinki, Finland

    Kristiina Uusi-Rauva, Aija Kyttälä & Anu Jalanko

  2. Division of Cell Biology, The Netherlands Cancer Institute, 1066 CX, Amsterdam, Netherlands

    Rik van der Kant & Jacques Neefjes

  3. Department of Human Genetics, David Geffen School of Medicine at UCLA, Gonda Neuroscience and Genetics Research Center, Los Angeles, CA, 90095-7088, USA

    Jouni Vesa

  4. Light Microscopy Unit, Institute of Biotechnology, University of Helsinki, PO Box 56, 00014, Helsinki, Finland

    Kimmo Tanhuanpää

  5. Minerva Foundation Institute for Medical Research, Biomedicum Helsinki, 2U, Tukholmankatu 8, 00290, Helsinki, Finland

    Vesa M. Olkkonen

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  1. Kristiina Uusi-Rauva
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  2. Aija Kyttälä
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Uusi-Rauva, K., Kyttälä, A., van der Kant, R. et al. Neuronal ceroid lipofuscinosis protein CLN3 interacts with motor proteins and modifies location of late endosomal compartments. Cell. Mol. Life Sci. 69, 2075–2089 (2012). https://doi.org/10.1007/s00018-011-0913-1

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