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The Parkin-Like Human Homolog of Drosophila Ariadne-1 (HHARI) Can Induce Aggresome Formation in Mammalian Cells and Is Immunologically Detectable in Lewy Bodies

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Abstract

Loss of functional Parkin is responsible for the death of midbrain dopaminergic neurons in human autosomal recessive juvenile parkinsonism. Since no cells express functional Parkin, it is unclear why other neuronal and non-neuronal populations are not also endangered. One possible explanation is that other neurons express a redundant ubiquitin–protein ligase (E3) that is absent from dopaminergic neurons. In this study, we demonstrate that human homolog of Drosophila ariadne-1 (HHARI) is a candidate for such a redundant function. In in vitro assays, HHARI binds to many of the same proteins as parkin, including CDCrel-1, synphilin-1, and CASK. In cell culture studies, HHARI forms aggresomes that are indistinguishable from those formed by parkin in terms of morphology, subcellular localization, incorporation of ubiquitin–proteasome components, and dependence on microtubules. In addition, endogenous HHARI is found in human Lewy bodies in both Parkinson’s disease and diffuse Lewy body disorder. Taken together, these data suggest that HHARI, and perhaps other Parkin-like E3 ligases, may serve redundant roles for parkin in different cell types.

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We are sad to report that Dr. Juan G. Cadena passed away on July 29, 2010.

Acknowledgments

We thank Dr. Philip Robinson for the ariadne constructs and for helpful discussion; Dr. Ted Dawson for the Parkin constructs; Dr. David Sharlin for help with statistical analysis; Dr. Rolf Karlstrom for help with imaging; and Drs. Philip Robinson, Rod Murphey, and Patricia Wadsworth for a critical reading of the manuscript. This work was supported by grants from the National Institutes of Health.

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Authors and Affiliations

  1. Molecular and Cellular Biology Program, University of Massachusetts, Amherst, MA, 01003, USA

    Sangram S. Parelkar, Juan G. Cadena, Chul Kim, Zhaohui Wang, Rachel Sugal & Lawrence M. Schwartz

  2. Pioneer Valley Life Sciences Institute, Springfield, MA, 01199, USA

    Brooke Bentley & Lawrence M. Schwartz

  3. Department of Pathology, Baystate Medical Center, Springfield, MA, 01199, USA

    Luis Moral

  4. Section of Ophthalmology and Neuroscience, Leeds Institute of Molecular Medicine, St. James’s University Hospital, Leeds, LS9 7TF, UK

    Helen C. Ardley

  5. Department of Biology, Morrill Science Center, University of Massachusetts, Amherst, MA, 01003, USA

    Lawrence M. Schwartz

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  1. Sangram S. Parelkar
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Correspondence to Lawrence M. Schwartz.

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Parelkar, S.S., Cadena, J.G., Kim, C. et al. The Parkin-Like Human Homolog of Drosophila Ariadne-1 (HHARI) Can Induce Aggresome Formation in Mammalian Cells and Is Immunologically Detectable in Lewy Bodies. J Mol Neurosci 46, 109–121 (2012). https://doi.org/10.1007/s12031-011-9535-1

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