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

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.

The ubiquitin ligase Ariadne-1 regulates NSF for neurotransmitter release

“…We identified 16 novel putative substrates of Ari-1 in Drosophila photoreceptor neurons in vivo by means of an unbiased proteomic approach. Remarkably, despite Ari-1 has been recently shown to regulate the positioning of the cell nucleus in muscles via a direct interaction with Parkin (21), as well as to interact with some Parkin substrates (21,23), there is no overlap between the substrates identified for Ari-1 and those previously identified for Parkin in flies (28). Taken together, the available data suggest that the 16 targets identified here are specifically regulated by Ari-1 in Drosophila photoreceptor neurons and that this E3 ligase has a wide functional repertoire.…”

“…However, despite its importance, no neuronal substrates have been reported so far. Only three Ari-1 substrates have been postulated, either in cultured cells or in vitro (20)(21)(22), while three Parkin substrates were reported to interact with Ari-1 in COS-1 cells (23). For this reason, with the aim to identify neuronal Ari-1 substrates, we took advantage of two methodologies developed by our lab (24).…”

ARIH2 Ubiquitinates NLRP3 and Negatively Regulates NLRP3 Inflammasome Activation in Macrophages

“…Several members of the RBR family have received considerable attention because they are implicated in protein aggregation diseases, including Parkinson's disease and Alzheimer's disease (30). For instance, parkin and ARIH1 have a tendency to be present in the hallmark protein aggregates of neurodegenerative diseases, and function as regulators of the aggregation-prone proteins (22,31). These findings led us to hypothesize that ARIH2 acts as a fine-tuning regulator of aggregate-prone proteins.…”

RBR E3‐ligases at work

“…Thus, it is likely that other cells express a redundant E3‐ligase to compensate for the loss of Parkin. HHARI is a likely candidate, as it binds many of the same protein partners, such as CDCrel‐1, synphilin‐1, and CASK , and may target synphilin‐1 and SIM2 for degradation in cells . Interestingly, HHARI is also found in Lewy bodies in dopaminergic neurons in PD, indicating that it cannot compensate the loss of Parkin activity in these cells .…”