Neurodegeneration and Neuroinflammation in Parkinson's Disease: a Self-Sustained Loop.

PURPOSE OF REVIEW: Neuroinflammation plays a significant role in Parkinson's disease (PD) etiology along with mitochondrial dysfunction and impaired proteostasis. In this context, mechanisms related to immune response can act as modifiers at different steps of the neurodegenerative process and justify the growing interest in anti-inflammatory agents as potential disease-modifying treatments in PD. The discovery of inherited gene mutations in PD has allowed researchers to develop cellular and animal models to study the mechanisms of the underlying biology, but the original cause of neuroinflammation in PD is still debated to date. RECENT FINDINGS: Cell autonomous alterations in neuronal cells, including mitochondrial damage and protein aggregation, could play a role, but recent findings also highlighted the importance of intercellular communication at both local and systemic level. This has given rise to debate about the role of non-neuronal cells in PD and reignited intense research into the gut-brain axis and other non-neuronal interactions in the development of the disease. Whatever the original trigger of neuroinflammation in PD, what appears quite clear is that the aberrant activation of glial cells and other components of the immune system creates a vicious circle in which neurodegeneration and neuroinflammation nourish each other. In this review, we will provide an up-to-date summary of the main cellular alterations underlying neuroinflammation in PD, including those induced by environmental factors (e.g. the gut microbiome) and those related to the genetic background of affected patients. Starting from the lesson provided by familial forms of PD, we will discuss pathophysiological mechanisms linked to inflammation that could also play a role in idiopathic forms. Finally, we will comment on the potential clinical translatability of immunobiomarkers identified in PD patient cohorts and provide an update on current therapeutic strategies aimed at overcoming or preventing inflammation in PD.

Acute respiratory failure and the kinetics of neutrophil recovery in pediatric hematopoietic cell transplantation: a multicenter study.

In this multicenter study, we investigated the kinetics of neutrophil recovery in relation to acuity and survival among 125 children undergoing allogeneic hematopoietic cell transplantation (allo-HCT) who required invasive mechanical ventilation (IMV). Recovery of neutrophils, whether prior to or after initiation of IMV, was associated with a significantly decreased risk of death relative to never achieving neutrophil recovery. A transient increase in acuity (by oxygenation index and vasopressor requirements) occurred among a subset of the patients who achieved neutrophil recovery after initiation of IMV; 61.5% of these patients survived to discharge from the intensive care unit (ICU). Improved survival among patients who subsequently achieved neutrophil recovery on IMV was not limited to those with peri-engraftment respiratory distress syndrome. The presence of a respiratory pathogen did not affect the risk of death while on IMV but was associated with an increased length of IMV (p < 0.01). Among patients undergoing HCT who develop respiratory failure and require advanced therapeutic support, neutrophil recovery at time of IMV and/or presence of a respiratory pathogen should not be used as determining factors when counseling families about survival.

Correction to: Acute respiratory failure and the kinetics of neutrophil recovery in pediatric hematopoietic cell transplantation: a multicenter study.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Mitochondrial proteolytic stress induced by loss of mortalin function is rescued by Parkin and PINK1.

The mitochondrial chaperone mortalin was implicated in Parkinson's disease (PD) because of its reduced levels in the brains of PD patients and disease-associated rare genetic variants that failed to rescue impaired mitochondrial integrity in cellular knockdown models. To uncover the molecular mechanisms underlying mortalin-related neurodegeneration, we dissected the cellular surveillance mechanisms related to mitochondrial quality control, defined the effects of reduced mortalin function at the molecular and cellular levels and investigated the functional interaction of mortalin with Parkin and PINK1, two PD-related proteins involved in mitochondrial homeostasis. We found that reduced mortalin function leads to: (1) activation of the mitochondrial unfolded protein response (UPR(mt)), (2) increased susceptibility towards intramitochondrial proteolytic stress, (3) increased autophagic degradation of fragmented mitochondria and (4) reduced mitochondrial mass in human cells in vitro and ex vivo. These alterations caused increased vulnerability toward apoptotic cell death. Proteotoxic perturbations induced by either partial loss of mortalin or chemical induction were rescued by complementation with native mortalin, but not disease-associated mortalin variants, and were independent of the integrity of autophagic pathways. However, Parkin and PINK1 rescued loss of mortalin phenotypes via increased lysosomal-mediated mitochondrial clearance and required intact autophagic machinery. Our results on loss of mortalin function reveal a direct link between impaired mitochondrial proteostasis, UPR(mt) and PD and show that effective removal of dysfunctional mitochondria via either genetic (PINK1 and Parkin overexpression) or pharmacological intervention (rapamycin) may compensate mitochondrial phenotypes.

Phosphorylation of HtrA2 by cyclin-dependent kinase-5 is important for mitochondrial function.

The role of the serine protease HtrA2 in neuroprotection was initially identified by the demonstration of neurodegeneration in mice lacking HtrA2 expression or function, and the interesting finding that mutations adjacent to two putative phosphorylation sites (S142 and S400) have been found in Parkinson's disease patients. However, the mechanism of this neuroprotection and the signalling pathways associated with it remain mostly unknown. Here we report that cyclin-dependent kinase-5 (Cdk5), a kinase implicated in the pathogenesis of several neurodegenerative diseases, is responsible for phosphorylating HtrA2 at S400. HtrA2 and Cdk5 interact in human and mouse cell lines and brain, and Cdk5 phosphorylates S400 on HtrA2 in a p38-dependent manner. Phosphorylation of HtrA2 at S400 is involved in maintaining mitochondrial membrane potential under stress conditions and is important for mitochondrial function, conferring cells protection against cellular stress.

A link between monoamine oxidase-A and apoptosis in serum deprived human SH-SY5Y neuroblastoma cells.

Increased monoamine oxidase (MAO) activity was recently shown to accompany apoptotic cell death of various neuronal cells following growth factor deprivation. Here we show that in serum deprived SH-SY5Y cells, MAO-A mRNA levels and catalytic activities are increased, linked with activation of the apoptotic executioner caspase-3. Importantly, specific inhibition of MAO-A activity resulted in loss of apoptotic cell morphology. Our study indicates that MAO catalytic activity is involved in apoptotic signalling in response to serum withdrawal in neuronal cells.

Human immunodeficiency virus type 1-specific immune responses in primates upon sequential immunization with adenoviral vaccine carriers of human and simian serotypes.

Two triple immunization vaccine regimens with adenoviral vectors with E1 deleted expressing Gag of human immunodeficiency virus type 1 were tested for induction of T- and B-cell-mediated-immune responses in mice and in nonhuman primates. The vaccine carriers were derived from distinct serotypes of human and simian adenoviruses that fail to elicit cross-neutralizing antibodies expected to dampen the effect of booster immunizations. Both triple immunization regimens induced unprecedented frequencies of gamma interferon-producing CD8(+) T cells to Gag in mice and monkeys that remained remarkably stable over time. In addition, monkeys developed Gag-specific interleukin-2-secreting T cells, presumably belonging to the CD4(+) T-cell subset, and antibodies to both Gag and the adenoviral vaccine carriers.

Induction of CD8+ T cells to an HIV-1 antigen upon oral immunization of mice with a simian E1-deleted adenoviral vector.

An E1-deleted adenoviral recombinant derived from the chimpanzee serotype 6 expressing a codon-optimized truncated form of gag of human immunodeficiency virus type 1 (HIV-1) was tested for induction of a transgene product-specific CD8+ T cell response upon oral immunization of mice. The vector was shown to induce gag-specific CD8+ T cells detectable at moderate frequencies of approximately 0.5-1.0% in the spleens and to provide partial protection in a surrogate challenge model based on intraperitoneal (i.p.) infection of mice with a vaccinia virus recombinant expressing gag (VVgag) of HIV-1. Frequencies of gag-specific CD8+ T cells could be augmented by using a different, i.e., heterologous, vaccine carrier based on a distinct recombinant virus or an alternative adenoviral serotype expressing the same form of gag for oral or systemic-booster immunization.

Structural analysis of PAX7 rearrangements in alveolar rhabdomyosarcoma.

In the pediatric cancer alveolar rhabdomyosarcoma, the common 2;13 and less frequent 1;13 translocations fuse PAX3 and PAX7, respectively, with FKHR to produce chimeric genes. To compare structural features of these rearrangements, we cloned and mapped a 64-kb genomic region containing PAX7 exons 5 through 8. With the use of Southern blot methodology, rearrangements of the 30-kb PAX7 intron 7 were detected in 9 of 9 PAX7-FKHR-positive cases. Similar to our t(2;13) studies, the t(1;13) breakpoints were randomly distributed within the seventh intron. In contrast with the > 90% frequency of reciprocal rearrangements in the t(2;13), reciprocal rearrangements involving the 3' PAX7 region were detected in only 4 of 9 cases. Furthermore, we detected PAX7-FKHR genomic amplification in 10 of 11 cases, in contrast with the < 5% frequency of PAX3-FKHR amplification. The differences in occurrence, reciprocity, and amplification between the PAX3-FKHR and PAX7-FKHR fusions indicate important differences in the mechanism of the two associated chromosomal translocation events.

Predominant expression of alternative PAX3 and PAX7 forms in myogenic and neural tumor cell lines.

PAX3 and PAX7 are closely related paired box family members expressed during early neural and myogenic development. Assay of PAX3 and PAX7 mRNA expression in embryonal rhabdomyosarcoma, neuroblastoma, Ewing's sarcoma, and melanoma cell lines revealed tumor-specific expression patterns similar to the corresponding embryonic lineages. Although the mammalian PAX3 and PAX7 genes were reported to contain eight exons, we found that the predominant PAX3 and PAX7 transcripts in these tumor lines contain previously uncharacterized ninth exons. These splicing events alter the COOH-terminal coding regions of the encoded products but do not alter the transcriptional activity as assayed using a reporter gene with a model PAX3/PAX7 binding site. However, the findings of nearly identical COOH-terminal regions within the corresponding genes of the avian and fish genomes suggest conserved functional roles for these regions that require further investigation.

Immune complexes in systemic sclerosis; detection by C1q binding, K-cell inhibition and Raji cell radioimmunoassays.

Thirty-four patients with systemic sclerosis (SS) were investigated for the presence of circulating immune complexes by means of a fluid phase C1q binding assay, K-cell inhibition assay and a Raji cell radioimmunoassay and the results compared with those obtained in 21 patients with systemic lupus erythematosus (SLE) and 52 normal healthy controls. Patients with SS showed an incidence of circulating immune complexes comparable to that found in SLE, with 20 patients (58.5%), giving a positive result with at least one of the assays. The presence of circulating immune complexes in patients with SS was found to be associated with both elevation of serum IgG and IgA levels and extensive visceral involvement by the disease. These findings raise the possibility that circulating immune complexes could be involved in the pathogenesis of SS.