The effects of pdr1, djr1.1 and pink1 loss in manganese-induced toxicity and the role of α-synuclein in C. elegans

Abstract

Parkinson's disease (PD) is a neurodegenerative brain disorder characterized by selective dopaminergic (DAergic) cell loss that results in overt motor and cognitive deficits. Current treatment options exist to combat PD symptomatology, but are unable to directly target its pathogenesis due to a lack of knowledge concerning its etiology. Several genes have been linked to PD, including three genes associated with an early-onset familial form: parkin, pink1 and dj1. All three genes are implicated in regulating oxidative stress pathways. Another hallmark of PD pathophysiology is Lewy body deposition, associated with the gain-of-function genetic risk factor α-synuclein. The function of α-synuclein is poorly understood, as it shows both neurotoxic and neuroprotective activities in PD. Using the genetically tractable invertebrate Caenorhabditis elegans (C. elegans) model system, the neurotoxic or neuroprotective role of α-synuclein upon acute Mn exposure in the background of mutated pdr1, pink1 or djr1.1 was examined. The pdr1 and djr1.1 mutants showed enhanced Mn accumulation and oxidative stress that was rescued by α-synuclein. Moreover, DAergic neurodegeneration, while unchanged with Mn exposure, returned to wild-type (WT) levels for pdr1, but not djr1.1 mutants expressing α-synuclein. Taken together, this study uncovers a novel, neuroprotective role for WT human α-synuclein in attenuating Mn-induced toxicity in the background of PD-associated genes, and further supports the role of extracellular dopamine in exacerbating Mn neurotoxicity.

Manganese disturbs metal and protein homeostasis in Caenorhabditis elegans

“…5). Conflicting reports exist as to whether MnCl 2 exposure results in frank dopaminergic cell loss in C. elegans , alone or in the context of α-synuclein expression 16, 21, 22 . Settivari et.…”

Untargeted metabolic profiling identifies interactions between Huntington's disease and neuronal manganese status

“…Subsequently, Mn content was quantified using our previously published methods 33 . Mn (fmol)/100 cell count ratios were determined by quantified protein levels as previously reported 21,22 .…”

Developmental exposure to manganese induces lasting motor and cognitive impairment in rats

“…The tissue was processed for inductively coupled plasma-mass spectrometry (ICP-MS) using the 8800 ICP-QQQ (Agilent, Santa Clara, CA) to determine the levels of Mn, Fe, Zn and Mg on a wet tissue basis (Bornhorst et al, 2014). Therefore, the tissue was weighed out into a perfluoroalkoxy alkane (PFA) microwave vessel and the sample had been digested by microwave (CEM, Kamp-Lintfort, Germany) after adding 10% hydrochloric acid and 10% nitric acid (both suprapur from VWR, Radnor, PA).…”