A novel manganese-dependent ATM-p53 signaling pathway is selectively impaired in patient-based neuroprogenitor and murine striatal models of Huntington's disease

Abstract

The essential micronutrient manganese is enriched in brain, especially in the basal ganglia. We sought to identify neuronal signaling pathways responsive to neurologically relevant manganese levels, as previous data suggested that alterations in striatal manganese handling occur in Huntington's disease (HD) models. We found that p53 phosphorylation at serine 15 is the most responsive cell signaling event to manganese exposure (of 18 tested) in human neuroprogenitors and a mouse striatal cell line. Manganese-dependent activation of p53 was severely diminished in HD cells. Inhibitors of ataxia telangiectasia mutated (ATM) kinase decreased manganese-dependent phosphorylation of p53. Likewise, analysis of ATM autophosphorylation and additional ATM kinase targets, H2AX and CHK2, support a role for ATM in the activation of p53 by manganese and that a defect in this process occurs in HD. Furthermore, the deficit in Mn-dependent activation of ATM kinase in HD neuroprogenitors was highly selective, as DNA damage and oxidative injury, canonical activators of ATM, did not show similar deficits. We assessed cellular manganese handling to test for correlations with the ATM-p53 pathway, and we observed reduced Mn accumulation in HD human neuroprogenitors and HD mouse striatal cells at manganese exposures associated with altered p53 activation. To determine if this phenotype contributes to the deficit in manganese-dependent ATM activation, we used pharmacological manipulation to equalize manganese levels between HD and control mouse striatal cells and rescued the ATM-p53 signaling deficit. Collectively, our data demonstrate selective alterations in manganese biology in cellular models of HD manifest in ATM-p53 signaling.

“Manganese-induced neurotoxicity: a review of its behavioral consequences and neuroprotective strategies”

“…Manganism is a syndrome similar to Parkinson’s disease (PD), characterized by psychiatric and cognitive deficits and motor impairment [27, 28]. Mn is also a putative environmental modifier of Huntington’s disease (HD) [29–31]. The symptoms caused by the accumulation of Mn include dystonia, bradykinesia and rigidity due to damage to dopaminergic (DAergic) neurons and gliosis [12, 32].…”

“…Transcription factors’ localization, such as NF-κB and NF - E2 - related factor 2 (Nrf2), is affected [43, 44]. Of particular interest, Mn-induced p53 phosphorylation, as well as upregulation of p53 levels, have been shown to be important events in cellular response to Mn exposure both in vivo and in vitro, possibly contributing to neuronal apoptosis [31, 45–47]. Endoplasmic reticulum (ER) stress is another factor that may lead to Mn-induced apoptosis [48].…”

Reduced bioavailable manganese causes striatal urea cycle pathology in Huntington's disease mouse model

“…We previously reported prodromal deficits in striatal Mn accumulation and altered responses of the proteome, metabolome, dopamine metabolism, p53 signaling, and dendritic morphology in human and mouse neuronal cells and HD mouse model brain tissue exposed to Mn [1–3]. There are subtle but significant reductions in cortical Mn levels in patients [4].…”

iPSC-based drug screening for Huntington׳s disease

“…In this study the A 2A R-selective agonists protected MSNs through the cAMP/PKA-dependent pathway (67). Also observed in human HD NSCs is a deficit is manganese-dependent activation of p53 (68). …”