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Cold Spring Harbor Perspectives in... Mar 2018Multiple sclerosis (MS) is a chronic inflammatory demyelinating disease of the central nervous system (CNS), which gives rise to focal lesions in the gray and white... (Review)
Review
Multiple sclerosis (MS) is a chronic inflammatory demyelinating disease of the central nervous system (CNS), which gives rise to focal lesions in the gray and white matter and to diffuse neurodegeneration in the entire brain. In this review, the spectrum of MS lesions and their relation to the inflammatory process is described. Pathology suggests that inflammation drives tissue injury at all stages of the disease. Focal inflammatory infiltrates in the meninges and the perivascular spaces appear to produce soluble factors, which induce demyelination or neurodegeneration either directly or indirectly through microglia activation. The nature of these soluble factors, which are responsible for demyelinating activity in sera and cerebrospinal fluid of the patients, is currently undefined. Demyelination and neurodegeneration is finally accomplished by oxidative injury and mitochondrial damage leading to a state of "virtual hypoxia."
Topics: Brain; Demyelinating Diseases; Disease Progression; Humans; Inflammation; Multiple Sclerosis; Nerve Degeneration
PubMed: 29358320
DOI: 10.1101/cshperspect.a028936 -
Disease Models & Mechanisms Oct 2020The global burden of neurodegenerative diseases underscores the urgent need for innovative strategies to define new drug targets and disease-modifying factors. The... (Review)
Review
The global burden of neurodegenerative diseases underscores the urgent need for innovative strategies to define new drug targets and disease-modifying factors. The nematode has served as the experimental subject for multiple transformative discoveries that have redefined our understanding of biology for ∼60 years. More recently, the considerable attributes of have been applied to neurodegenerative diseases, including amyotrophic lateral sclerosis, Alzheimer's disease, Parkinson's disease and Huntington's disease. Transgenic nematodes with genes encoding normal and disease variants of proteins at the single- or multi-copy level under neuronal-specific promoters limits expression to select neuronal subtypes. The anatomical transparency of affords the use of co-expressed fluorescent proteins to follow the progression of neurodegeneration as the animals age. Significantly, a completely defined connectome facilitates detailed understanding of the impact of neurodegeneration on organismal health and offers a unique capacity to accurately link cell death with behavioral dysfunction or phenotypic variation Moreover, chemical treatments, as well as forward and reverse genetic screening, hasten the identification of modifiers that alter neurodegeneration. When combined, these chemical-genetic analyses establish critical threshold states to enhance or reduce cellular stress for dissecting associated pathways. Furthermore, can rapidly reveal whether lifespan or healthspan factor into neurodegenerative processes. Here, we outline the methodologies employed to investigate neurodegeneration in and highlight numerous studies that exemplify its utility as a pre-clinical intermediary to expedite and inform mammalian translational research.
Topics: Aging; Animals; Animals, Genetically Modified; Behavior, Animal; Caenorhabditis elegans; Disease Models, Animal; Humans; Nerve Degeneration
PubMed: 33106318
DOI: 10.1242/dmm.046110 -
Molecular Neurodegeneration Jul 2021Novel targets to arrest neurodegeneration in several dementing conditions involving misfolded protein accumulations may be found in the diverse signaling pathways of the... (Review)
Review
Novel targets to arrest neurodegeneration in several dementing conditions involving misfolded protein accumulations may be found in the diverse signaling pathways of the Mammalian/mechanistic target of rapamycin (mTOR). As a nutrient sensor, mTOR has important homeostatic functions to regulate energy metabolism and support neuronal growth and plasticity. However, in Alzheimer's disease (AD), mTOR alternately plays important pathogenic roles by inhibiting both insulin signaling and autophagic removal of β-amyloid (Aβ) and phospho-tau (ptau) aggregates. It also plays a role in the cerebrovascular dysfunction of AD. mTOR is a serine/threonine kinase residing at the core in either of two multiprotein complexes termed mTORC1 and mTORC2. Recent data suggest that their balanced actions also have implications for Parkinson's disease (PD) and Huntington's disease (HD), Frontotemporal dementia (FTD) and Amyotrophic Lateral Sclerosis (ALS). Beyond rapamycin; an mTOR inhibitor, there are rapalogs having greater tolerability and micro delivery modes, that hold promise in arresting these age dependent conditions.
Topics: Animals; Humans; Nerve Degeneration; Neurodegenerative Diseases; TOR Serine-Threonine Kinases
PubMed: 34215308
DOI: 10.1186/s13024-021-00428-5 -
Molecular Neurobiology Jun 2018Methylene blue (MB) is a well-established drug with a long history of use, owing to its diverse range of use and its minimal side effect profile. MB has been used... (Review)
Review
Methylene blue (MB) is a well-established drug with a long history of use, owing to its diverse range of use and its minimal side effect profile. MB has been used classically for the treatment of malaria, methemoglobinemia, and carbon monoxide poisoning, as well as a histological dye. Its role in the mitochondria, however, has elicited much of its renewed interest in recent years. MB can reroute electrons in the mitochondrial electron transfer chain directly from NADH to cytochrome c, increasing the activity of complex IV and effectively promoting mitochondrial activity while mitigating oxidative stress. In addition to its beneficial effect on mitochondrial protection, MB is also known to have robust effects in mitigating neuroinflammation. Mitochondrial dysfunction has been identified as a seemingly unifying pathological phenomenon across a wide range of neurodegenerative disorders, which thus positions methylene blue as a promising therapeutic. In both in vitro and in vivo studies, MB has shown impressive efficacy in mitigating neurodegeneration and the accompanying behavioral phenotypes in animal models for such conditions as stroke, global cerebral ischemia, Alzheimer's disease, Parkinson's disease, and traumatic brain injury. This review summarizes recent work establishing MB as a promising candidate for neuroprotection, with particular emphasis on the contribution of mitochondrial function to neural health. Furthermore, this review will briefly examine the link between MB, neurogenesis, and improved cognition in respect to age-related cognitive decline.
Topics: Animals; Cognition; Humans; Methylene Blue; Mitochondria; Nerve Degeneration; Neurogenesis; Neuroprotection
PubMed: 28840449
DOI: 10.1007/s12035-017-0712-2 -
Journal of Neuroinflammation Dec 2019Metabolic dysfunction and neuroinflammation are increasingly implicated in Parkinson's disease (PD). The pentose phosphate pathway (PPP, a metabolic pathway parallel to...
BACKGROUND
Metabolic dysfunction and neuroinflammation are increasingly implicated in Parkinson's disease (PD). The pentose phosphate pathway (PPP, a metabolic pathway parallel to glycolysis) converts glucose-6-phosphate into pentoses and generates ribose-5-phosphate and NADPH thereby governing anabolic biosynthesis and redox homeostasis. Brains and immune cells display high activity of glucose-6-phosphate dehydrogenase (G6PD), the rate-limiting enzyme of the PPP. A postmortem study reveals dysregulation of G6PD enzyme in brains of PD patients. However, spatial and temporal changes in activity/expression of G6PD in PD remain undetermined. More importantly, it is unclear how dysfunction of G6PD and the PPP affects neuroinflammation and neurodegeneration in PD.
METHODS
We examined expression/activity of G6PD and its association with microglial activation and dopaminergic neurodegeneration in multiple chronic PD models generated by an intranigral/intraperitoneal injection of LPS, daily subcutaneous injection of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) for 6 days, or transgenic expression of A53T α-synuclein. Primary microglia were transfected with G6PD siRNAs and treated with lipopolysaccharide (LPS) to examine effects of G6PD knockdown on microglial activation and death of co-cultured neurons. LPS alone or with G6PD inhibitor(s) was administrated to mouse substantia nigra or midbrain neuron-glia cultures. While histological and biochemical analyses were conducted to examine microglial activation and dopaminergic neurodegeneration in vitro and in vivo, rotarod behavior test was performed to evaluate locomotor impairment in mice.
RESULTS
Expression and activity of G6PD were elevated in LPS-treated midbrain neuron-glia cultures (an in vitro PD model) and the substantia nigra of four in vivo PD models. Such elevation was positively associated with microglial activation and dopaminergic neurodegeneration. Furthermore, inhibition of G6PD by 6-aminonicotinamide and dehydroepiandrosterone and knockdown of microglial G6PD attenuated LPS-elicited chronic dopaminergic neurodegeneration. Mechanistically, microglia with elevated G6PD activity/expression produced excessive NADPH and provided abundant substrate to over-activated NADPH oxidase (NOX2) leading to production of excessive reactive oxygen species (ROS). Knockdown and inhibition of G6PD ameliorated LPS-triggered production of ROS and activation of NF-кB thereby dampening microglial activation.
CONCLUSIONS
Our findings indicated that G6PD-mediated PPP dysfunction and neuroinflammation exacerbated each other mediating chronic dopaminergic neurodegeneration and locomotor impairment. Insight into metabolic-inflammatory interface suggests that G6PD and NOX2 are potential therapeutic targets for PD.
Topics: Animals; Cells, Cultured; Coculture Techniques; Dopaminergic Neurons; Female; Gene Knockdown Techniques; Inflammation; Inflammation Mediators; Mice; Mice, Inbred C57BL; Nerve Degeneration; Pentose Phosphate Pathway; Pregnancy; Rats; Rats, Inbred F344; Reactive Oxygen Species
PubMed: 31805953
DOI: 10.1186/s12974-019-1659-1 -
Radiologia 2022Distal nerve degeneration refers to the process of disintegration of a neuron or neuronal circuit as a consequence of distal damage. The end result of multiple...
OBJECTIVE
Distal nerve degeneration refers to the process of disintegration of a neuron or neuronal circuit as a consequence of distal damage. The end result of multiple etiologies, this finding is becoming common due to the increasing number of imaging tests done. This paper aims to define the different types of distal nerve damage, review the anatomy and function of the most commonly affected tracts, and illustrate distal nerve damage through diagrams and representative cases from routine practice.
CONCLUSION
Knowing the distant response that can be expected according to the topography of a neuronal lesion is crucial to avoid diagnostic errors. Axonal degeneration and transsynaptic degeneration can be both antegrade and retrograde. Studies of cerebral metabolism, perfusion sequences, and diffusion sequences are showing increasingly earlier changes related to the same process; radiologists need to be aware of these changes.
Topics: Diagnostic Imaging; Humans; Nerve Degeneration; Neurons; Peripheral Nervous System Diseases
PubMed: 35504680
DOI: 10.1016/j.rxeng.2022.01.001 -
Annual Review of Pathology Jan 2021Alzheimer's disease (AD) is a pervasive, relentlessly progressive neurodegenerative disorder that includes both hereditary and sporadic forms linked by common underlying... (Review)
Review
Alzheimer's disease (AD) is a pervasive, relentlessly progressive neurodegenerative disorder that includes both hereditary and sporadic forms linked by common underlying neuropathologic changes and neuropsychological manifestations. While a clinical diagnosis is often made on the basis of initial memory dysfunction that progresses to involve multiple cognitive domains, definitive diagnosis requires autopsy examination of the brain to identify amyloid plaques and neurofibrillary degeneration. Over the past 100 years, there has been remarkable progress in our understanding of the underlying pathophysiologic processes, pathologic changes, and clinical phenotypes of AD, largely because genetic pathways that include but expand beyond amyloid processing have been uncovered. This review discusses the current state of understanding of the genetics of AD with a focus on how these advances are both shaping our understanding of the disease and informing novel avenues and approaches for development of potential therapeutic targets.
Topics: Aging; Alzheimer Disease; Animals; Humans; Nerve Degeneration
PubMed: 33497263
DOI: 10.1146/annurev-pathmechdis-012419-032551 -
Cellular and Molecular Life Sciences :... Nov 2016An expanded polyglutamine (polyQ) tract at the amino-terminus of the androgen receptor (AR) confers toxic properties responsible for neuronal and non-neuronal... (Review)
Review
An expanded polyglutamine (polyQ) tract at the amino-terminus of the androgen receptor (AR) confers toxic properties responsible for neuronal and non-neuronal degeneration in spinal and bulbar muscular atrophy (SBMA), one of nine polyQ expansion diseases. Both lower motor neurons and peripheral tissues, including skeletal muscle, are affected, supporting the notion that SBMA is not a pure motor neuron disease but a degenerative disorder of the neuromuscular system. Here, we review experimental evidence demonstrating both nerve and muscle degeneration in SBMA model systems and patients. We propose that polyQ AR toxicity targets these components in a time-dependent fashion, with muscle pathology predominating early and motor neuron loss becoming more significant at late stages. This model of pathogenesis has important therapeutic implications, suggesting that symptoms arising from degeneration of nerve or muscle predominate at different points and that directed interventions targeting these components will be variably effective depending upon disease progression.
Topics: Animals; Humans; Motor Neurons; Muscle, Skeletal; Nerve Degeneration; Neuromuscular Diseases; Peptides; Receptors, Androgen
PubMed: 27188284
DOI: 10.1007/s00018-016-2275-1 -
Physiological Reports Jan 2024Iron accumulates in the neural tissue during peripheral nerve degeneration. Some studies have already been suggested that iron facilitates Wallerian degeneration (WD)... (Review)
Review
Iron accumulates in the neural tissue during peripheral nerve degeneration. Some studies have already been suggested that iron facilitates Wallerian degeneration (WD) events such as Schwann cell de-differentiation. On the other hand, intracellular iron levels remain elevated during nerve regeneration and gradually decrease. Iron enhances Schwann cell differentiation and axonal outgrowth. Therefore, there seems to be a paradox in the role of iron during nerve degeneration and regeneration. We explain this contradiction by suggesting that the increase in intracellular iron concentration during peripheral nerve degeneration is likely to prepare neural cells for the initiation of regeneration. Changes in iron levels are the result of changes in the expression of iron homeostasis proteins. In this review, we will first discuss the changes in the iron/iron homeostasis protein levels during peripheral nerve degeneration and regeneration and then explain how iron is related to nerve regeneration. This data may help better understand the mechanisms of peripheral nerve repair and find a solution to prevent or slow the progression of peripheral neuropathies.
Topics: Humans; Peripheral Nervous System Diseases; Nerve Degeneration; Peripheral Nerves; Wallerian Degeneration; Neurons
PubMed: 38176709
DOI: 10.14814/phy2.15908 -
Cells Nov 2021Mitochondria are a unique intracellular organelle due to their evolutionary origin and multifunctional role in overall cellular physiology and pathophysiology. To meet... (Review)
Review
Mitochondria are a unique intracellular organelle due to their evolutionary origin and multifunctional role in overall cellular physiology and pathophysiology. To meet the specific spatial metabolic demands within the cell, mitochondria are actively moving, dividing, or fusing. This process of mitochondrial dynamics is fine-tuned by a specific group of proteins and their complex post-translational modifications. In this review, we discuss the mitochondrial dynamics regulatory enzymes, their adaptor proteins, and the effect of acetylation on the activity of fusion and fission machinery as a ubiquitous response to metabolic stresses. Further, we discuss the role of intracellular cytoskeleton structures and their post-translational modifications in the modulation of mitochondrial fusion and fission. Finally, we review the role of mitochondrial dynamics dysregulation in the pathophysiology of acute brain injury and the treatment strategies based on modulation of NAD-dependent deacetylation.
Topics: Acetylation; Animals; Cytoskeleton; Humans; Mitochondrial Dynamics; Mitochondrial Proteins; Nerve Degeneration; Protein Processing, Post-Translational
PubMed: 34831252
DOI: 10.3390/cells10113031