3: Therapeutic Approaches to Brain Repair Flashcards
(OBJ) Discuss the clinical features, pathophysiology and molecular mechanisms involved in Huntington.
Clinical features:
–Uncontrolled movements (chorea) as altered function of basal ganglia
Pathophysiology:
–Loss of medium spiny neurons in caudate and putamen
Molecular mechanism:
- -Expansion of unstable trinucleotide repeat (CAG) in Huntington gene
- -Proposed mechanism of expansion – “slippage” in repeated region during DNA replication –> increase number of CAGs (glutamines)
List six possible mechanisms of neuronal loss in Huntington’s disease.
- Toxic “gain of function” by mutant protein
- Transcriptional interference
- Toxicity of Huntingtin protein fragments
- Altered axonal transport
- Altered mitochondrial function/energetics
- Altered Ca homeostasis
(OBJ) Discuss the clinical features, pathophysiology and molecular mechanisms involved in Parkinson’s disease.
Clinical features:
- -Most common basal ganglia disorder (over 1 million cases in US)
- -Constant tremor, limb rigidity, less spontaneous movement
Pathophysiology:
–Lose > 50% of dopaminergic neurons in substantia nigra
Molecular mechanisms:
- -Lewy Bodies – aggregates of α-synuclein, ubiquitin, Parkin; might be toxic or protective (not known yet)
- -Loss of function of ubiquitin/proteosomal degradation mechanism -> toxicity of accumulated proteins OR abnormal protein accumulation
Define neurotrophic factor. Give some examples.
AKA neurotrophin
A target-derived molecule that is produced and released in limited quantities that supports the survival, growth, and differentiation of neurons during development, and their survival and function in the adult
–Typically bind to TRK receptors
–Produced in “pro” form, must be processed
–“Pro” form binds p75 -> cell death
–“Mature” form binds Trk -> survival
–Most neurons stimulated by multiple neurotrophic factors in their environment
Examples:
- -Neurotrophins (NGF, BDNF, NT-3, NT-4/5)
- -Glial-derived neurotrophic factor (GDNF, persephin, neurturin, artemin)
What is a Campenot chamber?
A compartmented tissue culture set-up for evaluating growth of neurons and aspects of retrograde transport
–Neurons place in center compartment, send out neurites under walls of divider
Used for in vitro analysis of NGF action
Add neutrotrophic factor to peripheral compartment -> Show that peripheral uptake and retrograde transport of neurotrophin and its receptor are required for survival
(OBJ) List the 5 mechanisms behind effective treatments of Parkinson’s disease.
Replacement of neurotransmitters Re-balancing neuronal circuits Virus-mediated gene delivery Prevent or slow loss of neurons using neurotrophic factors Transplantation
(OBJ) Explain the mechanisms behind effective treatments of Parkinson using replacement of neurotransmitters.
Replacement of neurotransmitters
- Oral L-DOPA/carbidopa therapy for Parkinson’s (widely used)
- Implant encapsulated dopamine or dopamine-secreting cells
(OBJ) Explain the mechanisms behind effective treatments of Parkinson by re-balancing neuronal circuits.
“Re-balance” the neuronal circuits
- Surgical manipulation - partial pallidotomy (benefit temporary?)
- Deep brain stimulation (DBS): reversible; potential for broad application
- -Parkinson’s: inhibit subthalamic with high frequency stimulation; *side effect - increase in impulsive behavior
(OBJ) Explain the mechanisms behind effective treatments of Parkinson using virus-mediated gene delivery.
Virus-mediated delivery of GAD enzyme gene –> increased GABA synthesis –> inhibition of subthalamic nucleus
- -Safety concerns
- -Several types of viruses used (adenovirus, AAV, retrovirus); advantages and disadvantages to each
- -Initial efforts have mixed success
(OBJ) Explain the mechanisms behind effective treatments of Parkinson using neurotrophic factors.
Goal: prevent or slow loss of neurons
–Example: GDNF (glial-derived) -> GFRa receptors -> couple to RET receptor -> intracellular signaling (MAP kinase, PI3K, PLC)
Mixed success in clinical trials – delivery is major hurdle
(OBJ) Describe the clinical features (2), pathophysiology (3) and molecular mechanisms (2) involved in Alzheimer.
Clinical features:
- -Most common dementia (5-10% over 65; 50% of those >85)
- -Also includes deficit in either visual-spatial orientation, abstract thinking, judgement, or language skills
Pathophysiology:
–Neuronal loss in cortex, hippocampus, amygdala, and cholinergic neurons in basal forebrain
Molecular mechanisms:
- -Protein aggregation / abnormal accumulation
1. Tau protein: normally a “spacer” between microtubules; hyperphosphorylated Tau forms fibrils -> intracellular **neurofibrillary “tangles”
2. Amyloid plaques - -Amyloid precursor protein (APP): have normal, ill-defined, function at synapses
- -Excessive APP cleavage by β-secretase and γ-secretase –> formation of AB40/42 –> aggregation –> amyloid plaques
- -γ-secretase = presenillin, nicastrin & 2 more localized in lipid rafts
(OBJ) Explain the mechanisms behind proposed and investigational treatments of Alzheimer. (5)
- -ACE inhibitors (arricept, tacrine): increase ACh levels -> help remaining ACh neurons in basal forebrain stay functional
- -Statins: decrease cholesterol -> affect lipid rafts; affect ApoE4 as a risk factor
- -γ-secretase inhibitors -> prevent formation/aggregation of AB40/42
- -Small molecule inhibitors of protein aggregation
- -Antibody-directed destruction of amyloid
(OBJ) Discuss issues involved in neuronal transplantation for treatment of neurodegenerative disorders. (3)
- Embryonic and fetal tissue
- -Advantage – repair damage not just symptoms
- -Limitations - safety; ethics; low survival rate - Autografts, xenografts, genetically modified cells (such as carotid body autotransplant or porcine dopaminergic cell xenografts)
- -Survival rate is high
- -Controversial - Stem Cells: cells with capacity for unlimited or prolonged self- renewal; can produce at least one type of differentiated cells
- -Neurogenesis in…
a. dentate gyrus of hippocampus
b. subventricular zone (SVZ)
Name one of the few drugs that has been approved to treat Huntington’s disease.
Tetrabenzadine
