Neuronal Cell Death II

Question 1

apoptosis

Answer 1

programmed cell death, characterised by an ordered disassembly of cell components, membrane blebbing, and cell shrinkage

Question 2

necrosis

Answer 2

uncontrolled cell lysis

Question 3

other cell death mechanisms

Answer 3

necroptosis
PARP1
autophagy

Question 4

intrinsic pathway for apoptosis

Answer 4

mitochondria are important
pro-apoptotic signals induce the formation of the permeability transition pore and stimulate release of cytochrome C from the mitochondria
cyt c activates caspases (cysteinyl aspartate specific proteases) caspases (3-9) regulate apoptosis

Question 5

extrinsic pathway for apoptosis

Answer 5

involves membrane death receptors and caspase 8 (involved in NDD)

Question 6

2 pro-survival signalling cascades

Answer 6

Ras-Raf-MEK-ERK1/2-RSK-CREB-P (upregulates bcl-2)-Bcl-2(survival tool)
PI3K/PDK-1 phosphorylates AKT - BAD-P (pro-survival)

CREB-P activated by cAMP/PKA

Question 7

absence of pro survival signals

Answer 7

unphosphorylated BAD
Bax Bax cause ion flux into the mitochondria
cytochrome c release from apopsome causes apoptosis

Question 8

lipid products of phosphoinositide-3-kinase (PI3K)

Answer 8

PtdIns(3)P
PtdIns(3,4)P2
PtdIns(3,4,5)P3

Question 9

PI3K groups

Answer 9

Class I PI3K (110kDa) divided into 2 groups:
IA - a/b/s - associate with 50-85kDa regulatory subunit
IB - y lacks N-terminal binding site for the regulatory subunit

Question 10

how does AKT promote neuronal survival

Answer 10

AKT - JIP1 - JNK (stops cell death pathway)
AKT - BAD - Bcl-xl
AKT - FKHR - FASL (stops neuronal death)

Question 11

what causes the failure of pro-survival neuronal signalling

Answer 11

loss of NT and neurotrophin input and breakdown of signalling component

decreased Ca2+/free radical - Ca2+-PI3K - ERK1/2 CREB or AKT/PKB (survival)
increase in Ca2+/free radical - Ca2+ - JNK - cJUN

Question 12

retinoid receptor heterodimer types

Answer 12

PPAR-RXR
RAR-RXR
TR-RXR

Question 13

what is retinoic acid derived from

Answer 13

Vitamin A (diet only)

Question 14

RA signalling

Answer 14

RA (in exosomes, fat)
CRABP (cellular RA binding protein)
in nucleus: RA binds to RXR RAR - binds to RARE - transcription/upregulated genes (ADAM10/glutamate R/process APP)
retinol - CRBP

Question 15

what traces the retinoids in the brain

Answer 15

HPLC - high performance liquid chromatography

Question 16

what occurs in retinoid deficient rats

Answer 16

loss of RAR-a and RALDH2 in the meninges (AD)
floppy limbs (no hindlimb stretching)
increased reactive astrocytosis (GFAP) and decreased RAR-a in cortex
increased AB after 12 months of retinoid deficient diet
RARbeta2 induced by RA in embryonic SC not adult SC - causes neurite growth
deficiencies in neurogenesis

Question 17

formation of cholinergic neurons via retinoid signalling

Answer 17

RARa and RARb (a/b agonists) signalling induces neural progenitors to proliferate and differentiate into cholinergic neurons
AD/stroke - define neurogenic pathways to replace the loss of neurons

Question 18

APP cleavage

Answer 18

a-secretase (non amyloidogenic) ADAM10 - upregulated by RA
y-secretase (amyloidogenic) downregulated by RA

Question 19

pathway analysis steps

Answer 19

take tissue from animal models treated with drugs
isolate RNA and sequence - analyse mRNA
pathway analysis
>50 retinoid pathways identified