Increased Mitochondrial Calcium Sensitivity and Abnormal Expression of Innate Immunity Genes Precede Dopaminergic Defects in Pink1-Deficient Mice

BACKGROUND: PTEN-induced kinase 1 (PINK1) is linked to recessive Parkinsonism (EOPD). Pink1 deletion results in impaired dopamine (DA) release and decreased mitochondrial respiration in the striatum of mice. To reveal additional mechanisms of Pink1-related dopaminergic dysfunction, we studied Ca²+ vulnerability of purified brain mitochondria, DA levels and metabolism and whether signaling pathways implicated in Parkinson\u27s disease (PD) display altered activity in the nigrostriatal system of Pink1⁻/⁻ mice. METHODS AND FINDINGS: Purified brain mitochondria of Pink1⁻/⁻ mice showed impaired Ca²+ storage capacity, resulting in increased Ca²+ induced mitochondrial permeability transition (mPT) that was rescued by cyclosporine A. A subpopulation of neurons in the substantia nigra of Pink1⁻/⁻ mice accumulated phospho-c-Jun, showing that Jun N-terminal kinase (JNK) activity is increased. Pink1⁻/⁻ mice 6 months and older displayed reduced DA levels associated with increased DA turnover. Moreover, Pink1⁻/⁻ mice had increased levels of IL-1β, IL-12 and IL-10 in the striatum after peripheral challenge with lipopolysaccharide (LPS), and Pink1⁻/⁻ embryonic fibroblasts showed decreased basal and inflammatory cytokine-induced nuclear factor kappa-β (NF-κB) activity. Quantitative transcriptional profiling in the striatum revealed that Pink1⁻/⁻ mice differentially express genes that (i) are upregulated in animals with experimentally induced dopaminergic lesions, (ii) regulate innate immune responses and/or apoptosis and (iii) promote axonal regeneration and sprouting. CONCLUSIONS: Increased mitochondrial Ca²+ sensitivity and JNK activity are early defects in Pink1⁻/⁻ mice that precede reduced DA levels and abnormal DA homeostasis and may contribute to neuronal dysfunction in familial PD. Differential gene expression in the nigrostriatal system of Pink1⁻/⁻ mice supports early dopaminergic dysfunction and shows that Pink1 deletion causes aberrant expression of genes that regulate innate immune responses. While some differentially expressed genes may mitigate neurodegeneration, increased LPS-induced brain cytokine expression and impaired cytokine-induced NF-κB activation may predispose neurons of Pink1⁻/⁻ mice to inflammation and injury-induced cell death

Biodiversity conservation as a promising frontier for behavioural science.

Human activities are degrading ecosystems worldwide, posing existential threats for biodiversity and humankind. Slowing and reversing this degradation will require profound and widespread changes to human behaviour. Behavioural scientists are therefore well placed to contribute intellectual leadership in this area. This Perspective aims to stimulate a marked increase in the amount and breadth of behavioural research addressing this challenge. First, we describe the importance of the biodiversity crisis for human and non-human prosperity and the central role of human behaviour in reversing this decline. Next, we discuss key gaps in our understanding of how to achieve behaviour change for biodiversity conservation and suggest how to identify key behaviour changes and actors capable of improving biodiversity outcomes. Finally, we outline the core components for building a robust evidence base and suggest priority research questions for behavioural scientists to explore in opening a new frontier of behavioural science for the benefit of nature and human wellbeing.We are grateful for funding from the Cambridge Conservation Initiative Collaborative Fund and Arcadia, RSPB, and the Gund Institute for Environment, University of Vermont. AB is supported by a Royal Society Wolfson Research Merit award. EEG was supported by a NERC studentship, grant number NE/L002507/1. We thank Paul C. Stern for helpful discussion and feedback

Nonlinear Analysis of tRNAs Nucleotide Sequences by Random Walks: Randomness and Order in the Primitive Informational Polymers

In order to test the hypothesis that the nucleotide sequences of the primitive informational polymers might not be chosen randomly and in the attempt to compare among taxa, we propose a comparison of computer-generated random sequences with tRNAs nucleotide sequences present in the bacterial and archaeal genomes, being tRNAs molecules possible "fossils" of the time (billions years ago) in which life arose. Our approach is based on the analysis of sequences of tRNAs described as random walks and the distances from the origin evaluated by the use of nonlinear indexes (largest Lyapunov exponent, entropy, BDS statistic). Six different tRNAs of Bacteria and Archaea (ten Archaea and ten Bacteria, thermophilic and mesophilic ones; n = 120), and computer-generated random sequences (n = 50) were studied. Our data show that tRNAs present indices statistical lower than the ones of computer-generated random data (tRNAs own a more ordered sequence than random ones: Lyapunov, p < 0.01; entropy, p < 0.05; BDS, p < 0.01). The observed deviation from pure randomness should be arisen from some constraints like the secondary structure of this biologic macromolecule and/or from a "frozen" stochastic transition, or even from the possible peculiar origin of tRNA by replication of older proto-RNA. Comparing between taxa, in the species studied, Bacteria present BDS and Base ratio (G+C)/(A+T) indexes statistically lower than in Archaea, together which a 20% of entropy increase. The analysis of a greater number of tRNAs and species will permit to explain if this finding, showing a higher randomness in the bacterial tRNAs sequences, is linked to the different base ratio, to the different environments in which the microorganisms live or to an evolutionary effect