12: HD Flashcards
2 specific subsets of neurons that become dysfunctional? what neurons are spared?
striatum: GABAergic medium spiny projection neurons. cortex: large pyramidal neurons in layers III, V, VI. interneurons spared.
number of CAG repeats correlates with?
age of onset. more repeats = earlier onset. progression of disease independent from CAG number
colocalization of htt with?
calreticulin, ER marker = lots of huntingtin found on ER surface
normal function of huntingtin: 5?
not completely known, but involved in: embryonic development, survival of adult neurons, BDNF transcription. vesicular and axonal transport. cellular response to stress.
htt roles + evidence
organization of extra-embryonic tissue + gastrulation. KO mice die. important for neurogenesis, maintaining neuronal identity.
mutant htt: development? what changes?
normal embyronic development, since mutant htt can exert all the functions of WT htt, during embryogenesis. adult: mutant htt displays partial loss of specific activities and acquires new toxic functions.
new toxic functions given by expanded poly Q region (5)
formation of protein aggregates, mitochondrial dysfunction, excitotoxicity, transcriptional dysregulation, aberrant cell signaling
mutant htt and vsicle transport?
strengthens htt interaction with HAP1, perturbs HAP1 binding to dynactin = impairs axonal transport = synaptic dysfunction and axonal degeneration
mutant htt and transcriptional regulation
polyQ expansion inhibits interaction with REST = REST enters nucleus, silences BDNF transcription = decreased survival of striatal neurons
mitochondrial dysfunction in HD
downregulation of complex II + III in respiratory chain = less ATP production, increase lactate production.
mitochondrial dysfunction in HD leads to (5)
altered metabolism. oxidative stress, increases susceptibility to apoptosis, excitotoxicity, axonal degeneration.
m Htt affects nuclear localization of?
nSREBP: master regulator of transcription for lipid metabolism; traps these TFs in cytosol
transcriptional dysreg in HD: m-htt binds? causes?
binds CBP aka creb binding protein; and other proteins with histone acetyltransferase activity and decreases activity = reduces gene transcirption
common mechanism of neurodegen?most important activator?
excitotoxicity: extra synaptic NMDAR … leads to increase in calcium
Summary of pathogenetic cellular events in HD (6)
phosphorylation at critical residues, proteolytic cleavage. aberrant cell signaling + stress response. increased excitotoxicity. impaired vesicle transport. mitochondrial dysfunction, cyt C release.
