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.
GM1: what? 4 roles?
essential regulator of cell signaling: cell cell adhesion, regulation of nuclear Ca homeostasis, modulation of cell signaling, regulation of synthesis + release of neurotrophins.
gangliosides act as? 3 roles?
lipid chaperones: modulate receptor activity, cell adhesion and myelin axon interactions, nuclear Ca homeostasis
how is GM1 changed in HD? problem?
GM1 is decreased in HD striatal cells and fibroblasts from HD patients. less GM1 = more apoptosis.
restoring normal GM1 levels in HD cells leads to 3 things?
AKT activation, huntingtin phosphorylation, decreased m htt toxicity
