Food supply fluctuations constrain group sizes of kangaroos and in turn shape their vigilance and feeding strategies

Seasonal variation in food resources and predation risk imposes major constraints on herbivores, which must adjust their behaviour to maximize their energy intake and survival. In seasonally driven landscapes, it is not yet clear what the primary drivers are that shape seasonal variation in vigilance and feeding rates. These rates have been shown to vary in relation to various environmental, social and individual factors, but many of these factors also vary through the year, due to variation in food supply. We studied wild female eastern grey kangaroos, Macropus giganteus, under low predation risk over a year to investigate whether vigilance and feeding rates varied seasonally and whether this variation was mainly driven by food quantity or quality, group size or individuals\u27 reproductive states. Both vigilance and feeding rates varied seasonally, as did food quantity and quality and group size. Vigilance, including antipredator (head orientation away from the group) and exclusive (i.e. vigilance without chewing) vigilance, decreased and feeding rate increased with increasing group size. However, because group size increased with food quality and quantity, food resources emerged as the primary driver of variation in behavioural strategies. These results suggest that the observed effects of group size on the trade-off between food acquisition and safety are in fact corollaries of the seasonal variation in food supply in our study system, in which the risk of predation on adults is low, and hence are by-products of the foraging choices made by kangaroos in response to the dynamics of the quantity and quality of food

Vesicle trafficking and pathways to neurodegeneration

Neurodegenerative diseases, encompassing a diverse range of inherited and sporadic disorders characterised by progressive loss of relatively discrete neuronal populations, are a significant and increasing challenge to human health and the global economy [1]. Despite significant advances in our understanding of the underlying ætiology of diseases such as Alzheimer’s, Parkinson’s and Huntington’s, and intense efforts targeting the development of disease-modifying therapies for these disorders, for the majority of people living with neurodegenerative conditions the prognosis remains poor [2,3,4]. Improving our knowledge of the underlying causes of neuronal loss in these disorders with the goal of developing novel disease-modifying therapies is thus a top priority for research, patient and care-giver communities

Subchondral chitosan/blood implant-guided bone plate resorption and woven bone repair is coupled to hyaline cartilage regeneration from microdrill holes in aged rabbit knees

SummaryObjectiveLittle is known of how to routinely elicit hyaline cartilage repair tissue in middle-aged patients. We tested the hypothesis that in skeletally aged rabbit knees, microdrill holes can be stimulated to remodel the bone plate and induce a more integrated, voluminous and hyaline cartilage repair tissue when treated by subchondral chitosan/blood implants.DesignNew Zealand White rabbits (13 or 32 months old, N = 7) received two 1.5 mm diameter, 2 mm depth drill holes in each knee, either left to bleed as surgical controls or press-fit with a 10 kDa (distal hole: 10K) or 40 kDa (proximal hole: 40K) chitosan/blood implant with fluorescent chitosan tracer. Post-operative knee effusion was documented. Repair tissues at day 0 (N = 1) and day 70 post-surgery (N = 6) were analyzed by micro-computed tomography, and by histological scoring and histomorphometry (SafO, Col-2, and Col-1) at day 70.ResultsAll chitosan implants were completely cleared after 70 days, without increasing transient post-operative knee effusion compared to controls. Proximal control holes had worse osteochondral repair than distal holes. Both implant formulations induced bone remodeling and improved lateral integration of the bone plate at the hole edge. The 40K implant inhibited further bone repair inside 50% of the proximal holes, while the 10K implant specifically induced a “wound bloom” reaction, characterized by decreased bone plate density in a limited zone beyond the initial hole edge, and increased woven bone (WB) plate repair inside the initial hole (P = 0.016), which was accompanied by a more voluminous and hyaline cartilage repair (P < 0.05 vs control defects).ConclusionIn a challenging aged rabbit model, bone marrow-derived hyaline cartilage repair can be promoted by treating acute drill holes with a biodegradable subchondral implant that elicits bone plate resorption followed by anabolic WB repair within a 70-day repair period

Deficiency of Parkinson's disease-related gene Fbxo7 is associated with impaired mitochondrial metabolism by PARP activation

The Parkinson's disease (PD)-related protein F-box only protein 7 (Fbxo7) is the substrate-recognition component of the Skp1-Cullin-F-box protein E3 ubiquitin ligase complex. We have recently shown that PD-associated mutations in Fbxo7 disrupt mitochondrial autophagy (mitophagy), suggesting a role for Fbxo7 in modulating mitochondrial homeostasis. Here we report that Fbxo7 deficiency is associated with reduced cellular NAD(+) levels, which results in increased mitochondrial NADH redox index and impaired activity of complex I in the electron transport chain. Under these conditions of compromised respiration, mitochondrial membrane potential and ATP contents are reduced, and cytosolic reactive oxygen species (ROS) production is increased. ROS activates poly (ADP-ribose) polymerase (PARP) activity in Fbxo7-deficient cells. PARP inhibitor restores cellular NAD(+) content and redox index and ATP pool, suggesting that PARP overactivation is cause of decreased complex I-driven respiration. These findings bring new insight into the mechanism of Fbxo7 deficiency, emphasising the importance of mitochondrial dysfunction in PD

Mutations and mechanism: how PINK1 may contribute to risk of sporadic Parkinson's disease

This scientific commentary refers to ‘Heterozygous PINK1 p.G411S increases risk of Parkinson’s disease via a dominant-negative mechanism’, by Puschmann et al. (doi:10.1093/ brain/aww261)

The role of SQSTM1 (p62) in mitochondrial function and clearance in human cortical neurons.

Sequestosome-1 (SQSTM1/p62) is involved in cellular processes such as autophagy and metabolic reprogramming. Mutations resulting in the loss of function of SQSTM1 lead to neurodegenerative diseases including frontotemporal dementia. The pathogenic mechanism that contributes to SQSTM1-related neurodegeneration has been linked to its role as an autophagy adaptor, but this is poorly understood, and its precise role in mitochondrial function and clearance remains to be clarified. Here, we assessed the importance of SQSTM1 in human induced pluripotent stem cell (iPSC)-derived cortical neurons through the knockout of SQSTM1. We show that SQSTM1 depletion causes altered mitochondrial gene expression and functionality, as well as autophagy flux, in iPSC-derived neurons. However, SQSTM1 is not essential for mitophagy despite having a significant impact on early PINK1-dependent mitophagy processes including PINK1 recruitment and phosphorylation of ubiquitin on depolarized mitochondria. These findings suggest that SQSTM1 is important for mitochondrial function rather than clearance

Intracellular pH Modulates Autophagy and Mitophagy

The specific autophagic elimination of mitochondria (mitophagy) plays the role of quality control for this organelle. Deregulation of mitophagy leads to an increased number of damaged mitochondria and triggers cell death. The deterioration of mitophagy has been hypothesized to underlie the pathogenesis of several neurodegenerative diseases, most notably Parkinson disease. Although some of the biochemical and molecular mechanisms of mitochondrial quality control are described in detail, physiological or pathological triggers of mitophagy are still not fully characterized. Here we show that the induction of mitophagy by the mitochondrial uncoupler FCCP is independent of the effect of mitochondrial membrane potential but dependent on acidification of the cytosol by FCCP. The ionophore nigericin also reduces cytosolic pH and induces PINK1/PARKIN-dependent and -independent mitophagy. The increase of intracellular pH with monensin suppresses the effects of FCCP and nigericin on mitochondrial degradation. Thus, a change in intracellular pH is a regulator of mitochondrial quality control

Mitophagy and Parkinson's disease: The PINK1–parkin link

The study of rare, inherited mutations underlying familial forms of Parkinson's disease has provided insight into the molecular mechanisms of disease pathogenesis. Mutations in these genes have been functionally linked to several key molecular pathways implicated in other neurodegenerative disorders, including mitochondrial dysfunction, protein accumulation and the autophagic-lysosomal pathway. In particular, the mitochondrial kinase PINK1 and the cytosolic E3 ubiquitin ligase parkin act in a common pathway to regulate mitochondrial function. In this review we discuss the recent evidence suggesting that the PINK1/parkin pathway also plays a critical role in the autophagic removal of damaged mitochondria–mitophagy. This article is part of a Special Issue entitled Mitochondria: the deadly organelle

The non-specific lethal complex regulates genes and pathways genetically linked to Parkinson’s disease

Genetic variants conferring risk for Parkinson's disease have been highlighted through genome-wide association studies, yet exploration of their specific disease mechanisms is lacking. Two Parkinson's disease candidate genes, KAT8 and KANSL1, identified through genome-wide studies and a PINK1-mitophagy screen, encode part of the histone acetylating non-specific lethal complex. This complex localises to the nucleus, where it has a role in transcriptional activation, and to mitochondria, where it has been suggested to have a role in mitochondrial transcription. In this study, we sought to identify whether the non-specific lethal complex has potential regulatory relationships with other genes associated with Parkinson's disease in human brain. Correlation in the expression of non-specific lethal genes and Parkinson's disease-associated genes was investigated in primary gene co-expression networks utilising publicly available transcriptomic data from multiple brain regions (provided by the Genotype-Tissue Expression Consortium and UK Brain Expression Consortium), whilst secondary networks were used to examine cell-type specificity. Reverse engineering of gene regulatory networks generated regulons of the complex, which were tested for heritability using stratified linkage disequilibrium score regression. Prioritised gene targets were then validated in vitro using a QuantiGene multiplex assay and publicly available chromatin immunoprecipitation-sequencing data. Significant clustering of non-specific lethal genes was revealed alongside Parkinson's disease-associated genes in frontal cortex primary co-expression modules, amongst other brain regions. Both primary and secondary co-expression modules containing these genes were enriched for mainly neuronal cell types. Regulons of the complex contained Parkinson's disease-associated genes and were enriched for biological pathways genetically linked to disease. When examined in a neuroblastoma cell line, 41% of prioritised gene targets showed significant changes in mRNA expression following KANSL1 or KAT8 perturbation. KANSL1 and H4K8 chromatin immunoprecipitation-sequencing data demonstrated NSL complex activity at many of these genes. In conclusion, genes encoding the non-specific lethal complex are highly correlated with and regulate genes associated with Parkinson's disease. Overall, these findings reveal a potentially wider role for this protein complex in regulating genes and pathways implicated in Parkinson's disease

Cancer and neurodegeneration: between the devil and the deep blue sea

Cancer and neurodegeneration are often thought of as disease mechanisms at opposite ends of a spectrum; one due to enhanced resistance to cell death and the other due to premature cell death. There is now accumulating evidence to link these two disparate processes. An increasing number of genetic studies add weight to epidemiological evidence suggesting that sufferers of a neurodegenerative disorder have a reduced incidence for most cancers, but an increased risk for other cancers. Many of the genes associated with either cancer and/or neurodegeneration play a central role in cell cycle control, DNA repair, and kinase signalling. However, the links between these two families of diseases remain to be proven. In this review, we discuss recent and sometimes as yet incomplete genetic discoveries that highlight the overlap of molecular pathways implicated in cancer and neurodegeneration