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Lecture 14

Repair and Regeneration; Neurodegenerative Disorders

What happens after axon of PNS neuron is damaged? Regeneration of axon in the PNS and re-innervation of peripheral
What cells are involved in the regeneration of peripheral nerves? Survived Schwann cells proliferate and provide the molecular environment for regeneration by secreting extracellular matrix molecules, cell adhesion molecules, and growth factors. Macrophages remove the cellular debris and secretes cytokines. Neurons inc
How is re-innervation accomplished? Accomplished by axons re-growing along the myelin sheath, as long as neuronal cell bodies are intact
What does the environment of the peripheral nervous system support? Supports axonal regeneration and re-innervation of targets after injury
What are activity dependent mechanisms essential for? Essential for successful re-innervation, elimination of polyneuronal innervation and functional recovery
What happens after axon of CNS neuron is damaged? Degeneration of axon in the CNS; no axonal growth. No re-innervation of central target
Why is axonal growth after injury inhibited in the CNS? The environment of the mature mammalian nervous system inhibits axonal growth. Axonal growth stops as soon as growth cone enters CNS.
What is the role of Nogo protein in CNS? Protein produced and released by oligodendrocytes in the CNS that blocks axonal regeneration
What happens after neuronal cell body is damaged in CNS? Neurodegeneration or replacement of damaged neurons as a result of neurogenesis in CNS (which is limited)
What conditions must be in place for neurogenesis to occur in CNS? New neurons originated from multipotent neural stem cells can replace damaged neurons. Neural stem cells have to be present within the certain brain regions. The local niche has to provide the environment for neurite's outgrowth, synaptogenesis, survival
What causes neuronal death? 11. Due to cell stress in the form of hypoxia (lack of oxygen to a tissue), excitotoxicity, neuroinflammation and/or deficit of the neurotrophic support. Ischemia is the decrease of blood supply to a tissue.
What mechanisms are involved in neuronal death and how are they different according to sex? Caspase-dependent (female) or caspase-independent (in males) mechanisms. Caspase-independent mech is initiated by poly polymerase-1 activation.
What is the role of glia cells in the CNS during local tissue damage? CNS glia (astrocyte, oligodendrocytes and microglia) actively oppose neuronal growth. Glial scar prevents axonal growth as it is a physical barrier. Astrocytes secrete molecules that inhibit axonal growth (semaphorin). Oligodendrocytes produce Nogo. Micro
What are the two regions in the mature mammalian CNS in which neural precursors (neural stem cells) are found? SVZ (subventricular zone) near the later wall of the lateral ventricles; SGZ (subgranular zone) of the DG of the hippocampus. Can also be found in subventricular zones of cerebellum, midbrain, spinal cord.
What do postmitotic neuroblasts in the SVZ in comparison to those in SGZ differentiate into? . Postmitotic neuroblasts migrate from SVZ to olfactory bulbs through the rostral migratory stream and differentiate into interneurons in the olfactory bulbs in the SVZ, NSCs generate a diverse cohort of new neurons, including GABAergic, dopamergic, and g
What happens to new survived neurons? . New survived neurons become integrated into existing functional synaptic circuits.
What mediates migration of new neurons in the CNS? New neurons in the adult mammalian brain migrate via specific pathway called rostral migratory stream (RMS) in which specialized glial cells secrete extracellular matrix molecules that facilitates migration of the new postmitotic neuroblasts.
What kind of neurogenesis occurs in human adults? Adult hippocampal neurogenesis occurs in humans and every other mammalian species examined. Adult SVZ neurogenesis occurs in humans and other mammalian.
What is Alzheimer's disease? What kind of onsets are there? Alzheimer's disease is characterized by profound episodic memory loss (inability to consolidate memory) and cognitive decline. Late onset (sporadic) is caused by environmental and genetic factors. Early onset (familial) is caused by mutations of the amylo
What brain regions are affected by Alzheimer's disease? Degeneration of neurons and their connectivity in hippocampus and cerebral cortex.
What role do the proteins tau and amyloid play in AD? Cytoskeletal protein tau which normally stabilizes the microtubules becomes hyperphosphorylated . This causes detachment from the microtubules leading to the formation of aggregates called neurofibrillary tangles inside the neurons. Amyloid beta protein o
. What is Parkinson's disease? Parkinson's disease is a hypokinetic movement disorder in which upper motor neurons have reduced excitatory input. It is age-related and the second most common neurodegenerative disorder.
What brain regions are affected by Parkinson's disease? Degeneration of substantia nigra's dopaminergic neurons and their projections to corpus striatum (caudate and putamen) occurs. inhibition of thalamic neurons that relay impulses to the upper motor neurons in the cortex. This causes both motor and non-mot
What is the role of Lewy bodies and ubiquitin in PD? Lewy bodies are cytoplasmic intraneuronal inclusions that contain proteins such as alpha-synuclein, ubiquitin, and Parkin proteins which are implicated in PD. Lewy bodies and lewy neurites are found in the substantia nigra and several other brain regions.
What is Huntington's disease? Huntington's disease is a hyperkinetic movement disorder in which upper motor neurons have lost regulatory influence from the basal ganglia. It is associated with mutation of Huntingtin.
. What brain regions are affected by Huntington's? Degeneration of striatal neurons (in putamen of the corpus striatum) and their projections to globus pallidus is associated with hyperkinesia that results from loss of restraining influence of basal ganglia on upper motor neurons due to the disinhibition
What role does the mutant Huntingtin have in HD? A mutation in the Huntingtin protein is caused by the expansion of a polyglutamine sequence of the Huntingtin protein as a result of the elongation and instability of a trinucleotide (CAG) on the short arm of Chromosome 4. The polyQ repeats cause protein
What is the proposed molecular mechanism for onset of HD? The polyQ repeats, protein misfolding and aggregation, disrupted BDNF production and signaling, degeneration of striatal neurons. BDNF is controlled by wild-type Huntingtin through mRNA production. It provides neurotrophic support to striatal neurons.
What occurs in neurodegenerative disorders such as Alzheimer's, Parkinson's, and Huntington? All involved the aggregation of misfolded proteins (amyloid beta, alpha-synuclein, huntingtin).
What common aspect do AD, PD, and HD defines their cause of pathology? All result in neuronal loss, synaptic dysfunction and axonal degeneration. Both genes and environmental factors determine the risk for development of these diseases.
Created by: stephurtado7
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