Tissue plasminogen activator prevents white matter damage following stroke

Tissue plasminogen activator protects white matter from stroke-induced lesions via the EGF-like domain and independent of proteolytic activity by promoting oligodendrocyte survival

Cytokine, sérine protéases et mort neuronale de type apoptotique

CAEN-BU Sciences et STAPS (141182103) / SudocSudocFranceF

Energy defects in Huntington's disease: Why “in vivo” evidence matters

International audienceHuntington's disease (HD) is an inherited progressive neurodegenerative disorder associated with involuntary abnormal movements (chorea), cognitive deficits and psychiatric disturbances. The most striking neuropathological change in HD is the early atrophy of the striatum. While the disease progresses, other brain structures also degenerate, including the cerebral cortex. Changes are also seen outside the brain, in particular weight loss/cachexia despite high dietary intake. The disease is caused by an abnormal expansion of a CAG repeat in the gene encoding the huntingtin protein (Htt). This mutation leads to the expression of a poly-glutamine stretch that changes the biological functions of mutant Htt (mHtt). The mechanisms underlying neurodegeneration in HD are not totally elucidated. Here, we discuss recent results obtained in patients, animal and cellular models suggesting that early disturbance in energy metabolism at least in part associated with mitochondrial defects may play a central role, even though all data are not congruent, possibly because most findings were obtained in cell culture systems or using biochemical analyses of post mortem tissues from rodent models. Thus, we put a particular focus on brain imaging studies that could identify biomarkers of energy defects in vivo and would be of prime interest in preclinical and clinical trials testing the efficacy of new therapies targeting energy metabolism in HD

Tissue-type plasminogen activator rescues neurones from serum deprivation-induced apoptosis through a mechanism independent of its proteolytic activity

International audienceAlthough the mechanism of action of tissue-type plasmino-gen activator (tPA) in excitotoxic necrosis is well documented , whether this serine protease can influence the apoptotic cascade remains a subject of debate. Here, we report that tPA protects cultured cortical neurones against apoptotic cell death induced by serum deprivation, an effect associated with a reduction of caspase-3 activation. Interestingly , blocking tPA proteolytic activity by either tPA stop or neuroserpin did not prevent this neuroprotection. Similarly , prevention of the interaction between tPA and its receptor low-density lipoprotein receptor-related protein (LRP) could not alter tPA anti-apoptotic activity. Interestingly , the survival-promoting effect of tPA was blocked by the phosphatidylinositol-3 (PI-3) kinase inhibitor, LY294002, but not by the mitogen-activated protein (MAP) kinase inhibitor, U0126. In conclusion, the present demonstration of an anti-apoptotic effect of tPA, independent of its enzymatic activity, reveals an additional level of complexity in our understanding of this critical mediator of brain physiology and pathology. Keywords: apoptosis, serine protease, serum deprivation, tissue-type plasminogen activator

The unlikely partnership between LRRK 2 and α‐synuclein in Parkinson's disease

International audienceAbstract Our understanding of the mechanisms underlying Parkinson's disease, the once archetypical nongenetic neurogenerative disorder, has dramatically increased with the identification of α‐synuclein and LRRK 2 pathogenic mutations. While α‐synuclein protein composes the aggregates that can spread through much of the brain in disease, LRRK 2 encodes a multidomain dual‐enzyme distinct from any other protein linked to neurodegeneration. In this review, we discuss emergent datasets from multiple model systems that suggest these unlikely partners do interact in important ways in disease, both within cells that express both LRRK 2 and α‐synuclein as well as through more indirect pathways that might involve neuroinflammation. Although the link between LRRK 2 and disease can be understood in part through LRRK 2 kinase activity (phosphotransferase activity), α‐synuclein toxicity is multilayered and plausibly interacts with LRRK 2 kinase activity in several ways. We discuss common protein interactors like 14‐3‐3s that may regulate α‐synuclein and LRRK 2 in disease. Finally, we examine cellular pathways and outcomes common to both mutant α‐synuclein expression and LRRK 2 activity and points of intersection. Understanding the interplay between these two unlikely partners in disease may provide new therapeutic avenues for PD

The unlikely partnership between LRRK2 and α-synuclein in Parkinson's disease

International audienceOur understanding of the mechanisms underlying Parkinson's disease, the once archetypical nongenetic neurogenerative disorder, has dramatically increased with the identification of α-synuclein and LRRK2 pathogenic mutations. While α-synuclein protein composes the aggregates that can spread through much of the brain in disease, LRRK2 encodes a multi-domain dual-enzyme distinct from any other protein linked to neurodegeneration. In this review, we discuss emergent datasets from multiple model systems that suggests these unlikely partners do interact in important ways in disease, both within cells that express both LRRK2 and α-synuclein as well as through more indirect pathways that might involve neuroinflammation. Although the link between LRRK2 and disease can be understood in part through LRRK2 kinase activity (phospho-transferase activity), α-synuclein toxicity is multi-layered and plausibly interacts with LRRK2 kinase activity in several ways. We discuss common protein interactors like 14-3-3s that may regulate αsynuclein and LRRK2 in disease. Finally, we examine cellular pathways and outcomes common to both mutant α-synuclein expression and LRRK2 activity and points of intersection. Understanding the interplay between these two unlikely partners in disease may provide new therapeutic avenues for PD

Sulfheme formation during homocysteine S-oxygenation by catalase in cancers and neurodegenerative diseases

International audienceAccumulating evidence suggests that abnormal levels of homocysteine are associated with vascular dysfunctions, cancer cell proliferation and various neurodegenerative diseases. With respect to the latter, a perturbation of transition metal homeostasis and an inhibition of catalase bioactivity have been reported. Herein, we report on some of the molecular bases for the cellular toxicity of homocysteine and demonstrate that it induces the formation of sulfcatalase, an irreversible inactive state of the enzyme, without the intervention of hydrogen sulfide. Initially, homocysteine reacts with native catalase and/or redox-active transition metal ions to generate thiyl radicals that mediate compound II formation, a temporarily inactive state of the enzyme. Then, the ferryl centre of compound II intervenes into the unprecedented S-oxygenation of homocysteine to engender the corresponding sulfenic acid species that further participates into the prosthetic heme modification through the formation of an unusual Fe( II) sulfonium. In addition, our ex cellulo studies performed on cancer cells, models of neurodegenerative diseases and ulcerative colitis suggest the likelihood of this scenario in a subset of cancer cells, as well as in a cellular model of Parkinson's disease. Our findings expand the repertoire of heme modifications promoted by biological compounds and point out another deleterious trait of disturbed homocysteine levels that could participate in the aetiology of these diseases

Zero echo time 17^{17}O-MRI reveals decreased cerebral metabolic rate of oxygen consumption in a murine model of amyloidosis

International audienceThe cerebral metabolic rate of oxygen consumption (CMRO$_2$) is a key metric to investigate the mechanisms involved in neurodegeneration in animal models and evaluate potential new therapies. CMRO$_2$ can be measured by direct $^{17}$O magnetic resonance imaging ($^{17}$O-MRI) of H$_2$$^{17}$O signal changes during inhalation of $^{17}$O-labeled oxygen gas. In this study, we built a simple gas distribution system and used 3D zero echo time (ZTE-)MRI at 11.7 T to measure CMRO$_2$ in the APP$_{swe}$/PS1$_{dE9}$ mouse model of amyloidosis. We found that CMRO$_2$ was significantly lower in the APP$_{swe}$/PS1$_{dE9}$ brain than in wild-type at 12–14 months. We also estimated cerebral blood flow (CBF) from the post-inhalation washout curve and found no difference between groups. These results suggest that the lower CMRO$_2$ observed in APP$_{swe}$/PS1$_{dE9}$ is likely due to metabolism impairment rather than to reduced blood flow. Analysis of the $^{17}$O-MRI data using different quantification models (linear and 3-phase model) showed that the choice of the model does not affect group comparison results. However, the simplified linear model significantly underestimated the absolute CMRO$_2$ values compared to a 3-phase model. This may become of importance when combining several metabolic fluxes measurements to study neuro-metabolic coupling

Matching Gene Expression with Hypometabolism after Cerebral Ischemia in the Nonhuman Primate

International audienceTo correlate brain metabolic status with the molecular events during cerebral ischemia, a cDNA array was performed after positron emission tomography scanning in a model of focal cerebral ischemia in baboons. Cluster analysis for the expression of 74 genes allowed the identification of 4 groups of genes. In each of the distinct groups, the authors observed a marked inflection in the pattern of gene expression when the CMRo was reduced by 48% to 66%. These patterns of coordinated modifications in gene expression could define molecular checkpoints for the development of an ischemic infarct and a molecular definition of the penumbra