Therapeutic Approaches to Neurodegenerative Disease

Question 1

general features of neurodegen diseases

Answer 1

slow progressive deterioration and neuronal loss in CNS

later onset

abnormal protein deposition/accumulation

preferentially affect specific neurons

Question 2

huntingtons disease

Answer 2

uncontrolled movements- chorea- as a result of altered basal ganglia

loss of medium spiny neurons in caudate and putamen

caused by expansion of unstable trinucleotide repeat (CAG) to greater than 35 repeats

proposed mechanism- slippage during replicatoin

Question 3

proposed mechanisms by which Huntingtons mutant protein interferes with function

Answer 3

transcriptional interference
overwhelming cellular degrading systems
toxicity of Hungintin protein fragments
altered axonal transport
altered mitochondrial function
altered Ca homeostasis

Question 4

treatments for huntingons

Answer 4

tetrabenzadine- helps with chorea

Cas9- bacterial nuclease is inserted w/ RNA guide to target a specific DNA sequence to delete some CAG repeats

DBS

Question 5

alzheimers disease

Answer 5

most common dementia

neuronal loss in cortex, hippocampus, cholinergic neruons in basal forebrain

caused by protein aggregation/abnormal accumulation

2 types-
Tau- normally a spacer between microtubules, hyperphosphorylated Tau forms fibrils- called “Tangles”

cause altered axonal transport

Amyloid
- amyloid precursor protein APP- found normally in synapses. excessive APP cleavage by B-secretase and y-secretase forms AB40/42- called “plaques”

causes inflammation

plaque- amyloid, APOE lipoproteins, and cholesterol

associated w/ decline:
memory and attention
language skills
visual spatial orientation
abstract thinking
judgement

Question 6

why is alzheimers affected by cholesterol

Answer 6

the APP cleaving enzyme y-secretase is found in lipid rafts, the amount of which is influenced by cholesterol

Question 7

what affect do AB fragments have on the brain?

Answer 7

effect neuronal morphology- shortened dendritic length and to reduce dendritic spine density

interfere w/ GABA and glutamate synapses

increase intracellular Ca post and pre synaptic

inflammation

Question 8

alzheimers treatments

Answer 8

y-secretase inhibitors- unsuccesful so far

AChase inhibtiors

NMDA inhibitors

Abs against amyloid protein

neurtrophic factors NGF and BDNF to combat cell loss

Question 9

parkinsons disease

Answer 9

common basal ganglia disorder

constant tremor, limb rigidity, less spontaneous movement

loss of over 50% of DA in substantia nigra

lewy bodies- protein aggregates (a-synuclein)- may be responsible for toxicity of cells

loss of function of ubiquitin/proteosome degradation mechanism

Question 10

parkinsons treatments

Answer 10

L-DOPA/carbidopa- carbidopa prevents increased DA synthesis in the periphery

eliminates symptoms (not tremors) but doesnt stop disease

rebalance basal ganglia via partial pallidotomy- effects only temporary

DBS- show increased risky behaviors- inactivate subthalamic nucleus

virus mediated gene delivery- mixed success but safety converns- trying to deliver GAD gene

Question 11

neurotrophic factors

Answer 11

prevent or slow loss of neurons

target derived molecule that is produced and released in limited quantities that support survival growth and differentiation of neurons

produced in “pro” form and need to be processed

(axon, dendrite growth, myelination, synapse formation)

Question 12

neurotrophins

Answer 12

NGF, BDNF, NT-3, NT4,5

campenot chamber- tissue culture for evaluating neuronal growth and transport

bind to TRK receptors

Question 13

signal transduction mechanisms

Answer 13

GDNF family- receptors that couple w/ RET- dimerize and autophosphorylate tyrosines

neurotrophin- TRK receptors- activate MAP, PLC, PI3K

Question 14

transplantation

Answer 14

embyronic or fetal tissue-
ad- repair tissue not symptoms
dis- safety, ethics, mortality

autografts-
ad- survival rate is high
dis- controversial

stem cells