Therapeutic approaches to neurodegen diseases

Question 1

huntingtons

Answer 1

loss of medium spiny neurons in caudate and putamen

Question 2

mechanism of huntingtons

Answer 2

slippage in repeated region during DNA replication–>increase in nuber of CAGs (glutamine)

problematic in huntington gene

Question 3

drug for huntingtons

Answer 3

tetrabenzdne

Question 4

altzehimers

Answer 4

loss of neurons in brain

cortical shrinkage, hippocamp shrinkage, enlargement of ventricles

Question 5

altz is associated with

Answer 5

protein aggregation and accumulation

Question 6

hallmarts of altz

Answer 6

neurofibrillary tangles–agg/accumulation of Tau protein fibrils

accumulation of amyloid containing plaques containing ab40/42 APP fragment

Question 7

Tau proteins

Answer 7

bind to microtubules and act as spacers to keep MT bundles in parallel

dissociate if instable MT or hyperphosed

form aggregates

Question 8

APP

Answer 8

transmembrane protein–>cleaved by secreatses (B & gama together)–>decrease synapse formation and release frag into extracellular space

frag is AB40/42 = NOT toxic

Question 9

gama secretase

Answer 9

complex of protein subunits
4 main proteins
-presnilin, nicastrin, aph1, pen2

reside in lipid rafts, so gama secretease is influenced by cholesteral levels

Question 10

AB aggregation

Answer 10

• accumulation of amyloid containing plaques
• inflammatory via activated microglia and astrocytes
• altered axonal transport (due to tau)
• altered synaptic activation
• altered intracellular Ca

Question 11

treatements of altz

Answer 11

acetycholinesterase inhibitors (talcrine)–>prolong and enhance Ach levels

small molec inhibitors–>prevent AB aggregation

antibodies against amyloid protein

Question 12

Parkinson’s Disease

Answer 12

loss of DA neurons in substantia nigra

Lewy bodies in neurons

Question 13

lewy bodies

Answer 13

protein aggregates that include a-synuclein & ubiquitin

Question 14

mech parkinsons

Answer 14

genetic mutations–>misfolded proteins–>toxic effects

lewy bodies-

• evidence for accumulation of proteins
• evidence for cell attempt to protect itself by sequestering toxic proteins

-mutations in genes encoding parkin and uchl-1 (proteins involved in delivery of proteins to pretasome for degradation)

Question 15

current therapy categories of altz

Answer 15

• reagents to prevent progression
• replacement of NT
• re-balance of neuronal circuits
• virus mediated gene delivery
• prevent or slow loss of neurons using neutrophic factors
• transplantation

Question 16

LDOPA/carbidopa therapy

Answer 16

LDOPA crosses BBB and makes DA on the other side

carbidopa is a DA carboxylase inhibitor that prevents increase in DA synthesis in periphery (does not cross BBB)

==>alleviates symptoms (not tremors), but odes not stop progression of disease

Question 17

surgical manipulations

Answer 17

partial pallidotomy (remove medial globus pallidus-temp benefit)

deep brain stimulation-functionally blocks regions

• -reversible, get optimal effect
• increase in impulsionand risky behavior

Question 18

different types of transplantation

Answer 18

• embryonic and fetal tissue
• autografts, xenogras, genetically modified cells
• stem cells

Question 19

neutrophic factor

Answer 19

target derived molecule that is produced and relased in quantities that supports survival, differentiation of neurons during dev, and survival and fx in adults

Question 20

neutrotrophin family

Answer 20

NGF
BDNF
NT3
NT4/5

Question 21

glial derived neurotrophic factor family

Answer 21

GDNF
persephin
neuroturin
artemin

Question 22

GDNF amily

Answer 22

ciupled to RET receptor–>dimerizes and autophos–>intracellular

Question 23

TRK receptor

Answer 23

dimerizes/autophos–>inside pathways

Question 24

TRKa

Answer 24

NGF

Question 25

TRK B

Answer 25

BDNF

Question 26

pro form

Answer 26

part cleaved off of protein–high affinity for p75R–>cell death