We investigate the molecular basis for the multi-functional nature of the presenilins as regulators of both intracellular ion homeostasis and intramembrane proteolysis. Our recent studies reveal that alterations in phosphatidyl-4,5-bisphosphate [known as PI 4,5 P2], a phosphoinositide lipid that controls several essential neural functions, contributes to the biochemical and cellular defects associated with AD.
This project is being conducted in close collaboration with the laboratory of Dr. Gilbert Di Paolo. We have conducted a high throughput cell-based assay and identified small molecules that can modulate BACE1 function via either a direct or indirect mechanism. Using these chemical probes, our laboratory is trying to understand the mechanism of BACE1 regulation by identifying cellular target s of these novel chemical modulators of BACE1. Furthermore, some of the small molecule hits are being developed as therapeutic candidates for the treatment of AD.
Complementary to the chemical biology approach, biochemical experiments to isolate the BACE1-haboring molecular complex have been conducted. Several BACE1-associated proteins, including members of the sorting nexin and sortilin families of protein trafficking modulators, have been identified. The function and pathological relevance of these proteins are being investigated. It is found in all races and ethnic groups. The nerve degeneration causes the subsequent degeneration of the muscles in the extremities.
CMT1 is a demyelinating neuropathy, and due to mutations in genes important in myelin formation, whereas CMT2 is axonal. NEFL encodes the neurofilament light NFL protein that we have previously shown to be a necessary component for the assembly of neuronal intermediate filaments.
Neuronal intermediate filaments form the intermediate filament network in neurons and are the predominant cytoskeletal structure in the axon. Neurofilamentous aggregates both in the neuronal cell bodies and axons are seen in patients with mutations in NEFL, as well as in other neurodegenerative diseases. We have studied the NEFL mutations in transfected cells and found that in both neuronal and non-neuronal cells, mutant NFL resulted in misassembly of the intermediate filament network. In neuronal cells, we found that the mutant proteins caused defects in axonal transport leading to degeneration of neurites.
Our studies showed a perfect correlation between pathogenic mutant NFL and the misassembly of filaments in the cultured cells. We are characterizing these mutations in more detail in transgenic animals. We hypothesize that inhibitors of neurofilament misassembly will lead to therapies for CMT.
Our cell and animal models will be useful for screening of potential therapeutic agents against the disease. We are also studying a family of cytoskeletal linker proteins called plakins. One of these plakins, BPAG1 was originally described as a component of the hemidesmosome in the epithelia, where it links the intermediate filaments to the extracellular matrix. Interestingly, the mutant mouse dystonia musculorum dt , which suffers from a severe hereditary sensory neuropathy is due to mutations in the BPAG1 gene.
Focal axonal swellings filled with neurofilaments, mitochondria and membrane bound dense bodies are hallmarks of the pathology of these mice and we are studying the neuronal form of this molecule. A closely related plakin called MACF1 Microtubule actin crosslinking factor is also highly expressed in the nervous system. We employ model systems of neuronal death to define the death pathways. We are particularly interested in the regulation of the caspases, the multi-membered family of death proteases that are central to the execution of death.
We have shown that the specificity of the death pathway is determined by the stimulus inducing death but also that there is flexibility in the pathways chosen for executing death.pinkchalzogu.ga
Neuronal Death by Accident or by Design
The dominant pathway depends on the relative concentrations of anti- and pro-apoptotic proteins. This illustrates that the maintenance of life and execution of death of a neuron is a delicate balance of the pro- and anti-apoptotic molecules in the cell, a balance that can be altered in disease. Our studies of oxidative stress mediated death show that cytokines can induce an autocrine mediated death. Down-regulation of superoxide dismutase 1 leads to activation of caspase-1 which releases the cytokine interleukin-1b and the cells undergo a peroxynitrite-dependent death.
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Thus, although caspase-1 has been defined as a non-apoptotic caspase with a role in inflammation, in response to specific death stimuli caspase-1 can activate a death pathway. It is important to understand the interaction that can occur between the cytokine signaling pathway and the death pathway to determine the appropriate intervention that will result in increased neuronal survival. Brain Donation Our ability to understand Alzheimer's disease is dependent upon studying brain tissue.
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Many people assume that human consciousness arose accidentally many eons ago from animal consciousness and that therefore we can find glimmers of the same sort of consciousness in the minds of animals. Consciousness is a slippery concept but the two prominent theories make different predictions as to which part of the brain will become active when a person becomes aware of an image; thus they can be tested by neuroscientists.
Neuroscience | Mind Matters
But it is not as if materialists have a big solution that others are stubbornly refusing to acknowledge. Graziano's approach is not new. Ancient philosophers thought the mind was fire not too long after the discovery of fire. Early modern philosophers thought the mind was a machine just as the machine age got started. Now suddenly it's a computer….
If consciousness is a mere tool of human sexual selection, it is mere plumage, a pretty enticement, of no meaning or import otherwise.
Decoding the neuroscience of consciousness
But then what becomes of Dr. It takes time to boot up and realize who you are, where you are, what time of day it is. First, you open your eyes and just see darkness. Darkness is different from nothing. Yes, they do very complicated things. We know that individual bees can fly mazes. They can remember scents. They can return to a distant flower. In fact, they can communicate with each other, through a dance, about the location and quality of a distant food source.
They have facial recognition and can recognize their beekeeper.
Their brains contain roughly a million neurons. By comparison, our brains contain about billion, so a hundred thousand times more. They have all the complicated components that we have in our brains, but in a smaller package. So yes, I do believe it feels like something to be a honey bee. It probably feels very good to be dancing in the sunlight and to drink nectar and carry it back to their hive.
I try not to kill bees or wasps or other insects anymore. Yes, their evolution diverged from us million years ago or so, but they share with us a lot of the basic metabolism and machinery of the brain. They have neurons, ionic channels, neurotransmitters, and dopamine just like we have. We also know Neanderthals had bigger brains than the Homo sapiens who lived near them in Europe. Their brain was maybe 10 percent larger than our brain. Did we just outbreed them? Were we more aggressive?
At the same time when Homo neanderthalensis became extinct—around 35, years ago— Homo sapiens domesticated the wolf and they became the two apex hunters. We became this ultra-efficient hunting cooperative because we now had the ability to be much more efficient at hunting down prey over long distances and exhausting them.
We have big brains and are, by some measure, the most intelligent species, at least in the short term. Maybe because they have flippers and live in the ocean, which is a relatively static environment. You need not only a brain, but also hands that can manipulate the environment. There are fascinating questions about how deep consciousness goes.
But if you take a more conceptual approach to consciousness, the evidence suggests there are many more systems that have consciousness—possibly all animals, all unicellular bacteria, and at some level maybe even individual cells that have an autonomous existence. But we know our intuition is fallible, which is why we need science to tell us what the actual state of the universe is.
The Internet and runaway AI will not have our value system. It may not care at all about humans. Why should it? Most scientists would dismiss panpsychism as ancient mythology. Why does this idea resonate for you? And we live in a universe where certain systems have consciousness. Why is that so? Why does the universe follow the laws of quantum mechanics? Suddenly the world is populated by entities that have conscious awareness, and that one simple principle leads to a number of very counterintuitive predictions that can, in principle, be verified.
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So it all comes down to how complex the system is? And for the human brain, how its neurons and synapses are wired together? It comes down to the circuitry of the brain. We know that most organs in your body do not give rise to consciousness. We also know that consciousness does not require your entire brain. You can lose 80 percent of your neurons. You can lose the little brain at the back of your brain called the cerebellum.
There was recently a year-old Chinese woman who discovered, when she had to get a brain scan, that she has absolutely no cerebellum. She never had one. It took her several years to learn how to walk and speak, but you can communicate with her.