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NEUROLOGICAL DISORDERS (Degenerative Disorders (Alzheimer's:
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NEUROLOGICAL DISORDERS
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Disorders of Development
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Down syndrome: caused not by inheritance of a faulty gene, but by possession of extra twenty-first chromosome.
- Down syndrome is congenital, which does not necessarily mean hereditary;
Congenital refers to a disorder that one is born with.
- It is characterized by moderate to severe mental retardation and often by physical abnormalities
- After age 30, the brain of a person with Down syndrome begins to degenerate in a manner similar to Alzheimer's disease.
Toxic chemical
Fetal alcohol syndrome: birth defect caused by ingestion of alcohol during pregnancy, especially during the 3rd to 4rth week; includes characteristic facial anomalies and faulty brain development that produces mental retardation.
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Degenerative Disorders
Alzheimer's:
- Degenerative brain disorder typically caused by misfolded beta-amyloid protein.
- Causes progressive memory loss, motor deficits, and eventual death
Beta-Amyloid (Abeta): Protein found in excessive amounts in brains of patients with Alzheimer's disease
Amyloid plaque: Extracellular deposit containing a dense core of beta-amyloid protein surrounded by degenerating axons and dendrites and activated microglia and reactive astrocytes.
Tau protein: Protein that is a component of microtubules, part of the cell's transport mechanism, Tau protein become hyper-phosphorylated (tons of phosphate groups get put on them) in Alzheimer's disease, which disrupt transport.
Neurofibrillary: Dying neuron containing intracellular accumulations of twisted Tau protein filaments that formerly served as cell’s internal skeleton.
Apolipoprotein E (ApoE):
- Glycoprotein that transports cholesterol in the blood and plays a role in cellular repair
- Presence of E4 allele of the ApoE gene increases risk of late-onset Alzheimer’s disease
Pharmacological Treatment:
- Acetylcholinesterase inhibitors, which just keep ACh around in the synapses longer,
- NMDA receptor antagonist, which probably just reduces excitotoxicity that is caused by dying neurons.
However, these drugs have no effect on process of neural degeneration and do not prolong patients’ survivalClinical trial with Alzheimer's patients attempted to destroy Beta-Amyloid by sensitizing the patient's immune systems to the protein
Beta-Amyloid precursor protein (APP): Protein that is the precursor for Beta-amyloid protein. The gene for this protein is located on chromosome 21, which is the one duplicated (triplicated) in down syndrome.
Secretase: class of enzymes that cut the Beta-amyloid precursor protein into smaller fragments, including Beta-amyloid.
- Presenilin: protein that forms part of the secretases that cut APP. When mutated, presenilin can cause Beta-amyloid precursor protein to be converted to the abnormal long form; may be a cause of Alzheimer’s disease
Parkinson's:
- Caused by degeneration of nigrostriatal dopamine system = the dopamine-secreting neurons of substantia migrants that send axons to basal ganglia
alpha-synuclein:
- Protein normally found in presynaptic membrane, where it is apparently involved in synaptic plasticity
- Abnormal accumulations are apparently causing dopamine neuron degeneration in Parkinson’s disease
Lewy body:
Abnormal circular structures with a dense core consisting of misfolded alpha-synuclein protein; found in the cytoplasm of nigrostriatal neurons in people with Parkinson’s disease.
Loss of function: (recessive mutation) said of genetic disorder caused by recessive gene that fails to produce protein that is necessary for good health (e.g., loss of or mutations in parkin gene can cause misfolded alpha-synuclein protein to not be degraded, which it normally is.)
Toxic gain of function: (dominant mutation) Genetic disorder caused by a dominant mutation that involves faulty gene that produces protein with toxic effects (e.g., a mutation in the alpha-synuclein gene can produce a protein that has toxic effects)
Parkin:
- Protein that plays a role in ferrying defective or misfolded proteins to the proteasomes
- Mutated parkin is a cause of familial Parkinson’s disease
Defective parkin fails to ubiquinate abnormal proteins, and they accumulate in the cell, eventually killing it
- Dopaminergic neurons are especially sensitive to this accumulation
Ubiquitin:
Protein that attaches itself to faulty or misfolded proteins and thus targets them for destruction by proteasomes
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Treatment:
Researches attempt to develop strategy of gene therapy to cure the diseases:
- One study introduced genetically modified virus into subthalamic nucleus of patients with Parkinson's disease
- Virus delivered gene for GAD, enzyme responsible for biosynthesis of the major inhibitory neurotransmitter, GABA
Huntington's disease:
- Inherited (purely genetic) disorder that causes degeneration of neurons in the basal ganglia
- Characterized by progressively more severe uncontrollable jerking movements, writhing movements, dementia, and finally death
Huntingtin (htt):
- Protein that may serve to facilitate the production and transport of brain-derived neurotrophic factor
- Abnormal huntingtin is the cause of Huntington’s disease
Multiple Sclerosis (MS):
- autoimmune demyelinating disease
- at scattered locations within CNS, myelin sheaths are attacked by the person's immune system, leaving behind hard patches of debris called sclerotic plaques
- Neural transmission of neural messages through demyelinated axons is interrupted
- because the damage occurs in white matter located throughout the brain and spinal cord, a wide variety of neurological disorders are seen.
- Most often form of MS is remitting-relapsing MS = progression than decrase
Treatments:
- Therapeutic procedure: lesioning the internal division of the globus pallidus (GPi), which is part of the basal ganglia.
GPi neurons are GABAergic and they act to inhibit motor behavior.
- The decreased release of dopamine in the striatum (caudate nucleus and putamen) that is seen in patients with Parkinson's disease causes an increase in activity of the GPi
- Damaging the GPi seems to relieve symptoms of Parkinson's disease by removing one of the brakes on motor behavior.
- Interferon-beta: protein that modulates responsiveness of the immune system
- Glatiramer acetate: (partially effective treatment) also known as cop axone or copolymer-1 --> put in peptides that look like Myelin, decoy approach
Amyotrophic lateral sclerosis (ALS): also known as Lou Gehrig’s Disease or motor neuron disease
- Degenerative disorder that attacks spinal cord and cranial nerve motor neurons
- Incidence of this disease is approximately 5 in 100,000
- Symptoms include spasticity (increased tension of muscles, causing stiff and awkward movements), exaggerated stretch reflexes, progressive weakness and muscular atrophy, and, finally, paralysis
10% of ALS cases are hereditary, 90% sporadic (cause unknown)
10/20% of hereditary case = caused by mutation in the gene that produces the enzyme superoxide dismutase 1 (SOD1), found on K 21
- This mutation causes a toxic gain of function that leads to protein misfolding and aggregation, impaired axonal transport, and mitochondrial dysfunction
Treatment:
- riluzole, a drug that reduces glutamate-induced excitotoxicity, probably by decreasing the release of glutamate
- Clinical trials found that patients treated with riluzole lived an average of approximately two months longer than those who received a placebo
- Average life span following a diagnosis is 2-4 years, but some people live much longer than that. For example, Stephan Hawking has lived with the disease for over 50 years.
Transmissible spongiform encephalopathy:
- Contagious brain disease, such as mad cow and Creurzfeldt-Jacob disease, whose degenerative process gives the brain a sponge-like appearance
- Caused by accumulation of misfolded prion protein
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Prion protein diseases can be genetic or sporadic (=idiopatic) and both forms can be transmitted to others by means of a simple misfolded prion protein.
Misfolded proteins often encourage more misfiling to occur. Thus, most neurodegenerative diseases can easily spread from neuron to neuron from brain to brain
Dementia:
- Loss of cognitive abilities such as memory, perception, verbal ability, and judgment that is caused by an organic brain disorder.
- Common causes are multiple strokes and Alzheimer's disease
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Seizure Disorders:
- prefered term for epilepsy
- Sometimes, if neurons that make up motor system are involved, a seizure can cause a convulsion
- But not all seizures cause convulsions; in fact, most do not
Partial Seizure:
Seizure that begins at a focus and remain localized, (not generalizing to the rest of the brain)
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Treatment:
- Anticonvulsant drugs: like Benzodiazepine, many of which work by increasing effectiveness of inhibitory synapse
Causes:
- Although some genetic factors can promote seizures, most of them are caused by non-genetic factors
- In the past many cases were considered to be idiopathic
- now with MRIs we discover that small brain abnormalities may be responsible
Symptoms
Aura: sensation that precedes a seizure
Its exact nature depends on the location of this seizure focus
Tonic phase: First phase of tonic-clonic seizure, all skeletal muscles are contracted
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Clonic phase: second phase of tonic-clonic seizure, rhythmic jerking movements