196,401 research outputs found
MtDNA-maintenance defects: syndromes and genes
No full textA large group of mitochondrial disorders, ranging from early-onset pediatric encephalopathic syndromes to late-onset myopathy with chronic progressive external ophthalmoplegia (CPEOs), are inherited as Mendelian disorders characterized by disturbed mitochondrial DNA (mtDNA) maintenance. These errors of nuclear-mitochondrial intergenomic signaling may lead to mtDNA depletion, accumulation of mtDNA multiple deletions, or both, in critical tissues. The genes involved encode proteins belonging to at least three pathways: mtDNA replication and maintenance, nucleotide supply and balance, and mitochondrial dynamics and quality control. In most cases, allelic mutations in these genes may lead to profoundly different phenotypes associated with either mtDNA depletion or multiple deletions.
Communicated by: Shamima Rahman
Presented at the Annual Symposium of the Society for the Study of Inborn Errors of Metabolism, Rome, Italy, September 6–9, 201
The "Janus-faced role" of autophagy in neuronal sickness: focus on neurodegeneration.
No full textThe mature brain is a highly dynamic organ that constantly changes its organization by destroying and forming new connections. Collectively, these changes are referred to as brain plasticity and are associated with functional changes, such as memory, addiction, and recovery of function after brain damage. Neuronal plasticity is sustained by the fine regulation of protein synthesis and organelle biogenesis and their degradation to ensure efficient turnover. Thus, autophagy, as quality control mechanism of proteins and organelles in neurons, is essential to their physiology and pathology. Here, we review recent several findings proving that defects in autophagy affect neuronal function and impair functional recovery after brain insults, contributing to neurodegeneration, in chronic and acute neurological disorders. Thus, an understanding of the molecular mechanisms by which the autophagy machinery is finely regulated might accelerate the development of therapeutic interventions in many neurological disorders for which no cure is available
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Breathe: Your Mitochondria Will Do the Rest… If They Are Healthy!
No full textDysfunctions of the mitochondrial electron transport chain cause severe, currently untreatable, diseases in humans. A new study by Jain et al. (2019) reports increased oxygen levels in the brain of complex-I-deficient mice. Reducing the O2 levels by hypoxia, carbon monoxide, or anemia, improved the clinical phenotype and prolonged the lifespan of the mouse model
Remote neurodegeneration: multiple actors for one play.
No full textRemote neurodegeneration significantly influences the clinical outcome in many central nervous system (CNS) pathologies, such as stroke, multiple sclerosis, and traumatic brain and spinal cord injuries. Because these processes develop days or months after injury, they are accompanied by a therapeutic window of opportunity. The complexity and clinical significance of remote damage is prompting many groups to examine the factors of remote degeneration. This research is providing insights into key unanswered questions, opening new avenues for innovative neuroprotective therapies. In this review, we evaluate data from various remote degeneration models to describe the complexity of the systems that are involved and the importance of their interactions in reducing damage and promoting recovery after brain lesions. Specifically, we recapitulate the current data on remote neuronal degeneration, focusing on molecular and cellular events, as studied in stroke and brain and spinal cord injury models. Remote damage is a multifactorial phenomenon in which many components become active in specific time frames. Days, weeks, or months after injury onset, the interplay between key effectors differentially affects neuronal survival and functional outcomes. In particular, we discuss apoptosis, inflammation, oxidative damage, and autophagy-all of which mediate remote degeneration at specific times. We also review current findings on the pharmacological manipulation of remote degeneration mechanisms in reducing damage and sustaining outcomes. These novel treatments differ from those that have been proposed to limit primary lesion site damage, representing new perspectives on neuroprotection
Il sacro in Martin Heidegger. I “venturi” e “l’ultimo Dio” (M. Viscomi)
No full textLa questione del Sacro, non immediatamente centrale all’interno della riflessione heideggeriana e degli studi critici su di essa formulati, svolge invece, nella proposta ermeneutica di Marco Viscomi, giovane dottore di ricerca in Filosofia, «una delle architravi della sua meditazione sull’Essere» (Viscomi 2018: 15), un termine imprescindibile in quanto, nella sua inattualità, continua a destare dal sonno dogmatico di un mondo sempre più funzionalizzato ogni essere umano che decide di incamminarsi sui sentieri del pensare originario, lasciandosi così interpellare dalla domanda filosofica fondamentale sull’essenza dell’umano, del divino e dell’intera realtà che lo circonda..
Nilotinib: from animal-based studies to clinical investigation in Alzheimer's disease patients
No full textSince their first description in the brains of patients suffering from Alzheimer’s disease (AD), more than 100 years ago, extracellular amyloid-β (Aβ) plaques and intracellular neurofibrillary tangles have been the principal focus of AD research. However, this focus has led to the failure of several long and promising clinical trials, and the efficacy of new Aβ-targeting drugs to slow down the disease progression is still controversial despite being successful in reducing the Aβ load.
Thus, despite the discouraging results, the lessons that have been learned from the Aβ debacle have prompted studies focusing on new molecular targets that regulate different cellular pathways and have formulated new hypotheses for investigating the involvement of different brain regions beyond the temporal lobe, including the hippocampal region
Improved insulin sensitivity associated with reduced mitochondrial complex IV assembly and activity
No full textMice lacking Surf1, a complex IV assembly protein, have 50-70% reduction in cytochrome c oxidase activity in all tissues yet a paradoxical increase in lifespan. Here we report that Surf1-/- mice have lower body (15%) and fat (20%) mass, in association with reduced lipid storage, smaller adipocytes, and elevated indicators of fatty acid oxidation in white adipose tissue (WAT) compared with control mice. The respiratory quotient in the Surf1-/- mice was significantly lower than in the control animals (0.83- 0.93 vs. 0.90-0.98), consistent with enhanced fat utilization in Surf1-/- mice. Elevated fat utilization was associated with increased insulin sensitivity measured as insulinstimulated glucose uptake, as well as an increase in insulin receptor levels (2-fold) and glucose transporter type 4 (GLUT4; 1.3-fold) levels in WAT in the Surf1-/- mice. The expression of peroxisome proliferator- activated receptor β-coactivator 1 (PGC-1α) mRNA and protein was up-regulated by 2.5- and 1.9- fold, respectively, in WAT from Surf1-/- mice, and the expression of PGC-1α target genes and markers of mitochondrial biogenesis was elevated. Together, these findings point to a novel and unexpected link between reduced mitochondrial complex IV activity, enhanced insulin sensitivity, and increased mitochondrial biogenesis that may contribute to the increased longevity in the Surf1-/- mice.-Deepa, S. S., Pulliam, D., Hill, S., Shi, Y., Walsh, M. E., Salmon, A., Sloane, L., Zhang, N., Zeviani, M., Viscomi, C., Musi, N., Van Remmen, H. Improved insulin sensitivity associated with reduced mitochondrial complex IV assembly and activity. FASEB J. 27, 1371-1380 (2013). www.fasebj.org
Distinct regulation of nNOS and iNOS by CB2 receptor in remote delayed neurodegeneration
No full textHemicerebellectomy results in remote delayed degeneration of precerebellar neurons. We have reported that such a lesion induces type 2 cannabinoid receptor (CB2) expression in precerebellar neurons and that stimulation of CB2, but not CB1, has neuroprotective effects. In this study, we found that in the same model, the CB2 agonist JWH-015 enhances neuronal nitric oxide synthase (nNOS) expression in axotomized neurons and that CB2-mediated neuroprotection is abrogated by pharmacological inhibition of nNOS. JWH-015 prevented the axotomy-induced upregulation of inducible NOS (iNOS) in astrocytes but had no effect on endothelial NOS (eNOS). In addition, we observed that JWH-015 significantly reduces hemicerebellectomy-induced neuroinflammatory responses and oxidative/nitrative stress. With regard to the signaling pathways of CB2/nNOS-mediated neuroprotection, we noted nNOS-dependent modulation of the expression of anti-oxidative (Hsp70) and anti-apoptotic (Bcl-2) proteins. These findings shed light on the interactions between the endocannabinoid and nitrergic systems after focal brain injury, implicating distinct functions of nNOS activation and iNOS inhibition in CB2 signaling, which protect neurons from axotomy-induced cell death.[...
The endocannabinoid system: A new entry in remote cell death mechanisms
No full textFunctional impairment after development of focal CNS lesions depends highly on damage that occurs in regions that are remote but functionally connected to the primary lesion site. These remote effects include cell death and structural changes, and they are important predictors of outcome in several pathologies, such as stroke, multiple sclerosis, and brain trauma. A greater understanding of the neuropathological mechanisms that exist in regions that are remote from focal primary lesions is therefore essential for the development of neuroprotective strategies. Endocannabinoids constitute a novel class of lipids that regulate mammalian cell apoptosis and the pathogenesis of neuroinflammatory and neurodegenerative diseases. In addition to well-described pharmacological actions in the brain, such as analgesia, hypokinesia, and hypothermia, endocannabinoids have been recently reported to control neuronal cell fate in various neuropathological conditions. Following brain injury, endocannabinoids are released, causing both protective and degenerative effects. Several hypotheses have been proposed to explain their role, but the mechanisms by which they act are largely unknown. New evidence indicates that the endocannabinoid system is a key participant in the determination of cell fate in remote cell death and its associated mechanisms. This review addresses recent findings on endocannabinoid function, focusing particularly on the relationships between the nitrergic, purinergic, and endocannabinoid systems.[...
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