Exam 1 Flashcards
Neurodegenerative disorders are characterized by…
- Progressive dysfunction
- death of neurons
- loss of white matter
selective vulnerability
definition
degeneration affects specfic systems, so not all neurons are equally vunerable
The two types of neurodegenerative diseases are
- Cognitive Disorders
- Motor disorders
Many neurodegenerative diseases have _____ types of disorder(s)
both or one
both
Neurodegenrative diseases goes hand in hand with
something that happens, could be a cause
protein aggregation inside and outside cells
Characteristics of neurodegeneration
- cell death of neurons
- process retraction
- synaptic loss
- synaptic dysfunction
- protein mislocalization within synapse
- metabolic imbalance
_____ ______ oppose all major changes from neurodegeneration
two words
homeostatic mechanisms
Neurons can die from
5
- insufficient trophic factors (aging)
- direct injury (TBI, Ischemia)
- dysregulation of internal milieu (elevated Ca2+, DNA damage, ROS)
- protein misfolding (sporadic AD & PD)
- genetic mutations (ALS)
Necrosis features
8 things
- Cytoplasm rupture
- chromatin dispersion
- loss of membrane integrity
- quick alteration of organelles
- no proteosynthesis
- histone & DNA degredation
- cellular lysis
- inflammation
Apoptosis features
8 things
- cellular shrings
- chromatin condensation
- membrane budding (membrane intact)
- intact/unchanged organelles
- de novo proteosynthesis
- activation of specific endonucleases
- apoptotic bodies
- no inflammation
Necrosis is __ cell death
unprogrammed
define
Necrosis
caused by, associated with, stopped by
- typically caused by exposure to high concentrations of oxidants, ionophores, or lesions
- associated with a cytotoxic edema & cellular swelling (bc water follows Na2+ into the cell)
- can be blocked by suppressing its stimulus
Synaptic NMDAR activity promotes
cell survival
Extrasynaptic NMDAR activity promotes
cell death
cell survival is promoted from
synaptic NMDAR activity
Glutamate binding to NMDAR leads to
increase of calcium in the cell
Ca2+ levels are regulated by
the mitochondria
describe
excitotoxicity
- Initiation Glu binds
- Amplification Ca2+ levels increase and proteases are activated. increased water in cell
- Expression ROS and RNA increase, production of ATP stopped, osmotic swelling
which death pathway when
Injury is high and calcium is high
Necrosis
death pathway when
injury is low/medium and calcium is low
apoptosis
calcium and injury levels for
necrosis
- calcium medium/high if injury high
- calcium very high if injury low
- when both calcium and injury high
calcium and injury levels for
apoptosis
- when injury is low, calcium low
- when injury is high, calcium low
- when medium injury, up to medium calcium
name
key molecules of neuronal apoptosis
Bcl-2 family proteins (Bax, Bak)
Apaf 1
Caspases
roles of Bcl-2 family members
- Anti-apoptotic: Bcl-2, Bcl-xL
- Proapoptotic inducers: Bax
- Proapoptotic potentiators: Bad, Bid, Bik
Bcl-2 functions by
preventing Bax from inducing apoptosis
define what and define function of
Caspases
Cys-Asp proteases which mean they cleave motifs after Asp
Classification of caspases
- Group I (inflammation mediator): 1
- Group II (effector): 3
- Group III (initiator): 8, 9
what it is and function
Apaf 1
- apoptotic protease activating factor 1
- transmits an apoptotic signal from mitchondria to capases
- activated by CARD domain
explain
Major apoptotic pathway in neurons
- FLIP activates caspase 8
- Bid activates and goes into mitochondria
- Diablo & Cyt C released from mitochondria
- Cyt C binds with Apaf-1 to make apoptosome
- apoptosome releases caspase 9
- caspase 8 and 9 induce making caspase 3
- caspase 3 makes apoptotic substrates
Extrinsic apoptosis is dependent on
- external receptor binding
- caspases
Instrinsic apoptosis depends on
- internal cellular stress
- loss of mitochondria
- caspases
Necroptosis
definition, requires, execuation
- induced by death receptors
- requires RIP1 and RIP3 activity
- requires caspase inhibition
- execution involves disintegration of membranes
steps
Execution of necroptosis
- RIP1 disassociates
- Na2+ increase in cell
- cell absorbs water
- edema then explodes
Major microfibules in axons
tau
Major microfibules in dendrites
MAP2
What regulates structure of dendritic spines
F-actin
the abnormal proteins that cause neurodegen disorders
do what
ruin presynaptic terminals and postsynaptic specializations
Mechanisms of neuronal dysfunction in Alzihmers
- Gene regulation
- cell surface receptions
- neurotransmitter release
- signalling cascases
- synaptic integrity
Mechanisms of neuronal dysfunction in Alzihmers
- Gene regulation
- cell surface receptions
- neurotransmitter release
- signaling cascades
- synaptic integrity
mechanisms of synaptic dysfunction
- excitotoxicity
- oxidative stress
- inflammation
- deregulation of proteostasis
ROS
produced by and causes what
- produced by ETC
- causes mtDNA muations
- decreased ATP
AD is associated with a loss of
synapses
define
mitochondrial fission
mitochondrial renewal, redistribution and proliferation into synapses
define
mitochondrial fusion
- mitochondiral interaction/communication with each other
- facilitating mitochondrial movement and distribution
central molecules in mitochondrial fission
- DRP1
- hFIS-1
central molecules in mitochondrial fusion
- Mfn-2
- OPA-1
dysfunction of mitochondrial energy metabolism leads to
- decreased ATP production
- impaired calcium control
- increase ROS
Sites of electrol leakage (superoxide generation) in mitochondira
- Complex 1 of ETC
- Complex 3 of ETC
- TCA cycle
areas and examples
areas with _ contain more mitochondira
areas with more demands for ATP
* presynaptic and postsynaptic terminals
* active growth cones
* axonal branches
* nodes of Ranvier
Mitochondria are made and degraded in the
(part of neuron)
soma