Student seminar 9/9- Huntington's Flashcards
Huntington’s Disease
neurodegenerative autosomal dominant disorder” that is shown by movement disorders and cognitive decline
Main physical shrinkage of brain…
degeneration of the striatum/ ventricles are enlarged due to a loss of brain mass
striatum normal role
striatum - plays large role in the motor and reward systems and cognitive processes
Damage comes from….
CAG repeats in DNA( varies in # on polymer chain= more than 36)
HTT gene
located on chromosome 4, everybody has two copies, mutated gene is what causes disease
Normal functions of cell
neuronal survival
development and differentation
gene regulation
cytoskeletal function
response to stress
synaptic function
Mechanism: aggregate formation**
- Mutant hungingtin with a polyglutamine expansion is cleaved in toxic fragments(high)
-Toxicity may arise from the oligomeric soluble species or from insoluble inclusions that sequester essential proteins
Mech: Transcriptional dysregulation
-Altered transcription of essential genes such as brain-derived neurotrophic factor (BDNF)
-Chromatin modifications
Altered protein homeostasis
-Proteasome dysfunction has been proposed as a mechanism of pathogenesis in HD
-Autophagic degradation is affected due to cargo sequestration or autophagosome transport
mech: mitochondrial dysfunction
-Defective Ca homeostasis
-altered protein transport
-impaired dynamics- increased fragmentation
-aberrant ROS production( free radicals)
-decreased ATP production
mech: altered synaptic plasticity
-Exicitotoxicity due to altered post-synaptic NMDAR( glutamate receptor), impacts glutamate uptake
-deficient delivery of synaptic vesicles and post-synaptic receptors
mech: Axonal transport defect
-impaired organelle transport
-impaired synaptic transmission from defective delivery of neurotransmitter receptors
Neuroglia dysfunction
-microglia secretes pro-inflammatory cytokines and chemokines
-impaired glutamate uptake of astrocytes
