Reduced Basal Autophagy and Impaired Mitochondrial Dynamics Due to Loss of Parkinson's Disease-Associated Protein DJ-1

BACKGROUND: Mitochondrial dysfunction and degradation takes a central role in current paradigms of neurodegeneration in Parkinson's disease (PD). Loss of DJ-1 function is a rare cause of familial PD. Although a critical role of DJ-1 in oxidative stress response and mitochondrial function has been recognized, the effects on mitochondrial dynamics and downstream consequences remain to be determined. METHODOLOGY/PRINCIPAL FINDINGS: Using DJ-1 loss of function cellular models from knockout (KO) mice and human carriers of the E64D mutation in the DJ-1 gene we define a novel role of DJ-1 in the integrity of both cellular organelles, mitochondria and lysosomes. We show that loss of DJ-1 caused impaired mitochondrial respiration, increased intramitochondrial reactive oxygen species, reduced mitochondrial membrane potential and characteristic alterations of mitochondrial shape as shown by quantitative morphology. Importantly, ultrastructural imaging and subsequent detailed lysosomal activity analyses revealed reduced basal autophagic degradation and the accumulation of defective mitochondria in DJ-1 KO cells, that was linked with decreased levels of phospho-activated ERK2. CONCLUSIONS/SIGNIFICANCE: We show that loss of DJ-1 leads to impaired autophagy and accumulation of dysfunctional mitochondria that under physiological conditions would be compensated via lysosomal clearance. Our study provides evidence for a critical role of DJ-1 in mitochondrial homeostasis by connecting basal autophagy and mitochondrial integrity in Parkinson's disease

Clinical-morphological and immunohistochemical characteristics of adenomas of the anterior pituitary lobe.

Purpose of work was to identify clinically relevant morphological and immunohistochemical features of pituitary adenomas.Цель работы − выделение клинически-значимых морфологических и иммуногистохимических особенностей аденом гипофиза

Трансплантация сердца и коронавирусная инфекция (COVID-19) в раннем послеоперационном периоде у пациента с гипертрофической обструктивной кардиомиопатией: клинический случай

Hypertrophic cardiomyopathy (HCM) is a disease that is usually unresponsive to conservative pathogenetic therapy. It does not have clearly developed surgical correction algorithms. Heart transplantation (HTx) is the sole therapeutic option when drug therapy is ineffective and surgical reduction of hypertrophic myocardium is not feasible. There are only sporadic reports in the literature about HTx for HCM. The novel coronavirus disease 2019 (COVID-19) pandemic has significantly affected the work of cardiac surgical units and, in particular, organ transplantation activities. This paper presents a clinical case of an HCM patient who underwent HTx, complicated by COVID-19 infection in the early postoperative period.Гипертрофическая кардиомиопатия – это заболевание, в большинстве случаев трудно поддающееся консервативной патогенетической терапии и не обладающее четко разработанными алгоритмами хирургической коррекции. Конечным вариантом лечения при неэффективности медикаментозной терапии и невозможности проведения хирургической редукции гипертрофированного миокарда является трансплантация сердца, о которой в литературе имеются лишь единичные сообщения. Пандемия новой коронавирусной инфекции существенно повлияла на работу кардиохирургических подразделений и в особенности на работу по пересадке органов. В данной статье представлен клинический случай пациента с гипертрофической кардиомиопатией, которому произведена трансплантация сердца, осложнившаяся инфекцией COVID-19 в раннем послеоперационном периоде

Impairment of PGC-1alpha expression, neuropathology and hepatic steatosis in a transgenic mouse model of Huntington's disease following chronic energy deprivation

We investigated the ability of AMP-activated protein kinase (AMPK) to activate PPARγ coactivator-1α (PGC-1α) in the brain, liver and brown adipose tissue (BAT) of the NLS-N171-82Q transgenic mouse model of Huntington's disease (HD). In the striatum of the HD mice, the baseline levels of PGC-1α, NRF1, NRF2, Tfam, COX-II, PPARdelta, CREB and ERRα mRNA and mitochondrial DNA (mtDNA), were significantly reduced. Administration of the creatine analog beta guanidinopropionic acid (GPA) reduced ATP and PCr levels and increased AMPK mRNA in both the cerebral cortex and striatum. Treatment with GPA significantly increased expression of PGC-1α, NRF1, Tfam and downstream genes in the striatum and cerebral cortex of wild-type (WT) mice, but there was no effect on these genes in the HD mice. The striatum of the untreated HD mice showed microvacuolation in the neuropil, as well as gliosis and huntingtin aggregates, which were exacerbated by treatment with GPA. GPA treatment produced a significant increase in mtDNA in the cerebral cortex and striatum of WT mice, but not in HD mice. The HD mice treated with GPA had impaired activation of liver PGC-1α and developed hepatic steatosis with accumulation of lipids, degeneration of hepatocytes and impaired activation of gluconeogenesis. The BAT in the HD mice showed vacuolation due to accumulation of neutral lipids, and age-dependent impairment of UCP-1 activation and temperature regulation. Impaired activation of PGC-1α, therefore, plays an important role in the behavioral phenotype, metabolic disturbances and pathology of HD, which suggests the possibility that agents that enhance PGC-1α function will exert therapeutic benefits in HD patients