Prolongation of metallothionein induction combats Aß and α-synuclein toxicity in aged transgenic Caenorhabditis elegans

Abstract

Neurodegenerative disorders (ND) like Alzheimer’s (AD), Parkinson’s (PD), Huntington’s or Prion diseases share similar pathological features. They are all age dependent and are often associated with disruptions in analogous metabolic processes such as protein aggregation and oxidative stress, both of which involve metal ions like copper, manganese and iron. Bush and Tanzi proposed 2008 in the ‘metal hypothesis of Alzheimer’s disease’ that a breakdown in metal homeostasis is the main cause of NDs, and drugs restoring metal homeostasis are promising novel therapeutic strategies. We report here that metallothionein (MT), an endogenous metal detoxifying protein, is increased in young amyloid ß (Aß) expressing Caenorhabditis elegans, whereas it is not in wild type strains. Further MT induction collapsed in 8 days old transgenic worms, indicating the age dependency of disease outbreak, and sharing intriguing parallels to diminished MT levels in human brains of AD. A medium throughput screening assay method was established to search for compounds increasing the MT level. Compounds known to induce MT release like progesterone, ZnSO 4 , quercetin, dexamethasone and apomorphine were active in models of AD and PD. Thioflavin T, clioquinol and emodin are promising leads in AD and PD research, whose mode of action has not been fully established yet. In this study, we could show that the reduction of Aß and α-synuclein toxicity in transgenic C. elegans models correlated with the prolongation of MT induction time and that knockdown of MT with RNA interference resulted in a loss of bioactivity.

Nutritive Manganese and Zinc Overdosing in Aging C. elegans Result in a Metallothionein‐Mediated Alteration in Metal Homeostasis

“…have shown the age‐dependent potential of supplemented Zn to increase and prolong metallothionein induction and thereby decrease proteotoxicity in amyloid β and α‐synuclein expressing worms. [ 58 ] Taken together, this indicates that the induction of metal dyshomeostasis seems to be alleviated during aging and in terms of PD due to altered regulation mechanisms, in turn, rendering organisms more susceptible to the toxicity of metal mixtures.…”

Redox-Active Metal Ions and Amyloid-Degrading Enzymes in Alzheimer’s Disease

“…However, further processes were stopped during the phase II/III trial since a toxic compound was detected during the manufacturing steps. Although it showed toxicity, CQ has recently been examined for its potential neuroprotective effect in C. elegans [142].…”

“…In particular, many chemical agents targeting both Cu(I/II) and Aβ or Cu(I/II) and ROS have been developed. Based on multifunctionality, a few chemical agents, although they have firstly been suggested as Cu(I/II) chelators, are still examined for their potentials as therapeutic agents for AD in various animals (Table 2) [142,[152][153][154]163,167].…”

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“…In spite of this considerable knowledge on the role played by MTs in longevity, modulation of their expression and testing in aged non-transgenic animals is still elusive, and this is a critical step toward utilizing these mechanisms for the treatment of age-related conditions in humans. In worm models of neurodegenerative disorders indirect induction of MTs by Zn, progesterone, quercetin, dexamethasone and apomorphine reduced the burden associated with Amyloid β and α-synuclein while knockdown of MTs resulted in a partial loss of bioactivity of these compounds [7]. However, these and most other known MT-inducing compounds are also non-specific inducers of Nrf2 expression or are known to interfere with many other pathways thus complicating their therapeutic translation based on the specific target.…”