Topic
Neurodegeneration
About: Neurodegeneration is a research topic. Over the lifetime, 21120 publications have been published within this topic receiving 1345543 citations.
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TL;DR: After a long lag period, therapeutic and other interventions based on a knowledge of redox biology are on the horizon for at least some of the neurodegenerative diseases.
Abstract: The brain and nervous system are prone to oxidative stress, and are inadequately equipped with antioxidant defense systems to prevent 'ongoing' oxidative damage, let alone the extra oxidative damage imposed by the neurodegenerative diseases. Indeed, increased oxidative damage, mitochondrial dysfunction, accumulation of oxidized aggregated proteins, inflammation, and defects in protein clearance constitute complex intertwined pathologies that conspire to kill neurons. After a long lag period, therapeutic and other interventions based on a knowledge of redox biology are on the horizon for at least some of the neurodegenerative diseases.
2,430 citations
TL;DR: The evidence suggests a pathophysiological link between TDP-43 and ALS, and neighboring mutations in a highly conserved region of TARDBP in sporadic and familial ALS cases.
Abstract: Amyotrophic lateral sclerosis (ALS) is a fatal motor neuron disorder characterized pathologically by ubiquitinated TAR DNA binding protein (TDP-43) inclusions. The function of TDP-43 in the nervous system is uncertain, and a mechanistic role in neurodegeneration remains speculative. We identified neighboring mutations in a highly conserved region of TARDBP in sporadic and familial ALS cases. TARDBPM337V segregated with disease within one kindred and a genome-wide scan confirmed that linkage was restricted to chromosome 1p36, which contains the TARDBP locus. Mutant forms of TDP-43 fragmented in vitro more readily than wild type and, in vivo, caused neural apoptosis and developmental delay in the chick embryo. Our evidence suggests a pathophysiological link between TDP-43 and ALS.
2,425 citations
TL;DR: This work shows that mammalian target of rapamycin (mTOR) is sequestered in polyglutamine aggregates in cell models, transgenic mice and human brains, and provides proof-of-principle for the potential of inducing autophagy to treat Huntington disease.
Abstract: Huntington disease is one of nine inherited neurodegenerative disorders caused by a polyglutamine tract expansion. Expanded polyglutamine proteins accumulate abnormally in intracellular aggregates. Here we show that mammalian target of rapamycin (mTOR) is sequestered in polyglutamine aggregates in cell models, transgenic mice and human brains. Sequestration of mTOR impairs its kinase activity and induces autophagy, a key clearance pathway for mutant huntingtin fragments. This protects against polyglutamine toxicity, as the specific mTOR inhibitor rapamycin attenuates huntingtin accumulation and cell death in cell models of Huntington disease, and inhibition of autophagy has the converse effects. Furthermore, rapamycin protects against neurodegeneration in a fly model of Huntington disease, and the rapamycin analog CCI-779 improved performance on four different behavioral tasks and decreased aggregate formation in a mouse model of Huntington disease. Our data provide proof-of-principle for the potential of inducing autophagy to treat Huntington disease.
2,335 citations
TL;DR: Mechanisms of BBB dysfunction in neurodegenerative disorders, notably Alzheimer's disease, are examined, and therapeutic opportunities relating to these neurovascular deficits are highlighted.
Abstract: The neurovascular unit (NVU) comprises brain endothelial cells, pericytes or vascular smooth muscle cells, glia and neurons. The NVU controls blood-brain barrier (BBB) permeability and cerebral blood flow, and maintains the chemical composition of the neuronal 'milieu', which is required for proper functioning of neuronal circuits. Recent evidence indicates that BBB dysfunction is associated with the accumulation of several vasculotoxic and neurotoxic molecules within brain parenchyma, a reduction in cerebral blood flow, and hypoxia. Together, these vascular-derived insults might initiate and/or contribute to neuronal degeneration. This article examines mechanisms of BBB dysfunction in neurodegenerative disorders, notably Alzheimer's disease, and highlights therapeutic opportunities relating to these neurovascular deficits.
2,256 citations
TL;DR: Important roles for ER-initiated cell death pathways have been recognized for several diseases, including hypoxia, ischemia/reperfusion injury, neurodegeneration, heart disease, and diabetes.
Abstract: Disturbances in the normal functions of the ER lead to an evolutionarily conserved cell stress response, the unfolded protein response, which is aimed initially at compensating for damage but can eventually trigger cell death if ER dysfunction is severe or prolonged. The mechanisms by which ER stress leads to cell death remain enigmatic, with multiple potential participants described but little clarity about which specific death effectors dominate in particular cellular contexts. Important roles for ER-initiated cell death pathways have been recognized for several diseases, including hypoxia, ischemia/reperfusion injury, neurodegeneration, heart disease, and diabetes.
2,146 citations