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Neurobiology of Disease > Exam 1: ALS > Flashcards

Exam 1: ALS Flashcards

1
Q

Lateral corticospinal tract

A

3/4

cross MEDULLA

LIMBS

LATERAL alpha-MN

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2
Q

Ventral corticospinal tract

A

1/4 axons

axons don’t cross

Neck, should, trunk

MEDIAL alpha-MN

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3
Q

Upper motor neuron disturbances

A

spasticity, weakness, enhanced deep tendon reflexes

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4
Q

Lower motor neuron disturbances

A

fasciculations, wasting, weakness

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5
Q

Who? Inheritance?

A

mostly Caucasian men

90% sporadic
10% familial dominance pattern

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6
Q

ALS symptoms

A 
Clumsy hand 
hoarse voice (dysarthria)
shoulder dysfunction
weak foot (drop foot)
difficulty walking (spastic gait)
exercise intolerance
fasciculation
respiratory insufficiency 
cognitive impairment
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7
Q

As ALS symptoms spread throughout the body

A

weigth loss, fatigue, exaggerated reflexes, decreased coordination

Bizarre affect, uncontrolled inappropriate crying and laughing, inappropriate responses

overlap with frontotemporal dementia

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8
Q

With progression

A

can’t walk, stand, eat, or breathe

relentless progression
50% die in 30 months symptom onset
20% survive 5-10 years

lack of sensory involvement

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9
Q

3 presentations of ALS

A

1) 70% limb onset
2) 25% bulbar onset- speech/swallowing, respiration, dysapnea
3) 5% trunk and/or respiratory onset

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10
Q

Typical pathological features: SOD1

A

SOD1 aggregates in spinal motor neurons (Familial)

TDP-43 redistribution to cytoplasmic inclusions in spinal motor neurons in sporadic ALS

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11
Q

3 types of ALS genes

A

1) alter proteostasis and protein quality control
2) disrupt RNA stability and function
3) disrupt cytoskeleton dynamics of MN

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12
Q

Theories and predictive factors of ALS

A

unknown

bets predictive factors: age and family hisotyr

unsubstantiated: viral infection and lyme disease

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13
Q

Inherited ALS: SOD1 mutation

A

autosomal dominant
free radical scavenging enzyme

mouse = hind limb weakness.

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14
Q

Inherited ALS: TAR DMP (TDP-43) and FUS

A

multifunctional proteins involved in gene expression transcription/translation/transport

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15
Q

Inherited ALS: OPTN

A

encodes optineurin

involved in regulation of NFkB

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16
Q

Inherited ALS: ALS2: Alisin mutation

A

rare, recessive

encodes alsin protein, involved in cycling G protein between GDP-GTP state. pathology not understood

17
Q

Chromosome 9p21 locus

A

GGGCC repeats on C9ORF72.
normal <16 while ALS patients have up to 1600. Patients present with aggressive disease, cognitive impairments toxicity not understood

18
Q

Mechanisms of Motor Neuron Death: Cu/Zn SOD1

A

mutations in SOD1 identified, loss of antioxidant thought to cuase injury by superoxide. SOD1 catalyzes conversion of superoxide to hydrogen peroxide and oxygen

SOD1 mice not rescued by wildtype SOD
SOD1 KO don’t have issue

Animal model DOES NOT support SOD1/free radical theory

mutant = toxic gain of function

19
Q

Mechanisms of Motor Neuron Death: Glia Cells

A

inflammation from microglial in response to SOD1 mutations

C9orf72 mutations associate with microglia activation

SOD1 mutations in oligodendrites induces demyelination

mutations impair astrocytes in buffering glutamate, promote excitotoxicity

mutant SOD1 slows antero/retrograde transport, no transport of RNA model

PROINFLAMMATORY CYTOKINES IN MICROGLIA

20
Q

Mechanisms of Motor Neuron Death: ER stress

A

ER stress from misfolded proteins inpeeds degrading and removing non functional proteins

disrupted ubiquitin-proteasome system and autophagy

21
Q

Mechanisms of Motor Neuron Death: Apoptotic factors

A

DNA fragmentation and elevated Bax

strengthened by data showing SOD1 mutants induce apoptosis

SOD1 mice have elevated Bad and Bax and decreased bcl-2/Bcl-xL

If you overexpress BCL2, delay onset

SOD1 mice show caspase activation (proteases), inhibition prolongs SOD1 life span

22
Q

Mechanisms of Motor Neuron Death: Intermediate filaments

A

neurofilament proteins form cytoskeleton, abnormal synthesis/accumulation

abnormal transport. Unclear if accumulation of NFs causes or is caused by blockage.

mRNA analysis shown reduced NF light mRNA

23
Q

Mechanisms of Motor Neuron Death: Defects in axonal transport

A

SOD1 mice = slow axon transport

mutations in dynactin (need for retrograde transport)

24
Q

Mechanisms of Motor Neuron Death: Excitotoxicity

A

40% sporadic ALS patients elevated CSF.

EAAT2 is reduced in 95% biopsies from ALS patients

Theory is aberrant splicing of EAAT2 in mRNA, making truncated proteins. Unclear since splices also found in normal tissue.

25
Q

Mechanisms of Motor Neuron Death: Growth Factors

A

vascular endothelial cell growth factor (VEGF) controls growth of blood vessels

KO mice for VEGF = motor neuron disease.

Intracerebroventricular injection of VEGF slows disease

clinical trials anticipated

26
Q

Mechanisms of Motor Neuron Death: Mitochondrial dysfunction

A

some version of SOD1 show vacuoles with damaged mitochondria.
not in all SOD1 versions

Creatine- enhances energy storage and slows progression in SOD1 mice. Failed in human clinical trials

27
Q

Main point: LOTS wrong in ALS. List all you can

A 
over excited
aberrant RNA metabolism
dysregulated vesicle transport
mitochondrial dysfunction
impaired DNA repair 
failure to clear glutamate (hyperexcited) 
axonopathy
disrupted cytoskeleton
bad quality control system 
NF accumulation
28
Q

Treatment: Glutamate modulators

A

Riluzole: blocks voltage dependent Na+ channels, inhibits glutamate release, blocks amino acid receptors.

increase in survival, but no difference in end morality

Also no benefit in strength and neurological function

29
Q

Treatment: Antioxidants

A

Edaravone: free radical scavenger

slowed symptom progression, no cure

Vitamin E also slow progression.

30
Q

Treatment: Energy Metabolism

A

Creatine/phospjocreatine- intracellular transporter of ATP from site of synthesis to location of use, helps energy production in mitochondria, maintains ATP levels.

Survival improved in SOD1 mice, ineffective in human clinical trials.

31
Q

Treatment: Antinflammatory Agents

A

Prostaglandins synthesized from arachidonic acid by COX2

induce release of glutamate from astrocytes- role in excitotoxicity

COX2 inhibitors helped neuronal survival in in vitro studies and SOD1 mice, failed human clinical trials

32
Q

Treatment: Neurotrophins

A

BDNF/GDNF/CNTF tested in multiple clinical trials. Failed to show response, produced adverse side effects (anorexia, nausea)

IGF-1 produced mixed results

more trials underway with stem cells, viral vectors, siRNA techniques

33
Q

Paper: Retrograde viral delivery of IGF-1 prolongs survival in mouse

A

GFP expression in lumber motor neurons

Disease onset/mortality delayed by delivery of trophic factors

AAV retrogradely transported from presynaptic to cell body/nuc

Results: IGF-1 treatment prolonged life of SOD1 mice, improved muscle performance, even when delivered after symptom onset. IGF-1 animals also maintained body weight and muscle mass longer

34
Q

Paper: VEGF delivery with retrogradely transported lentivector prolongs survival in a mouse ALS model

A

pseduotyping-engineering alternative viral envelopes to maintain tropism.

Plasmids with envelope, packaging, and transfer gene (viral genome) are used to make non-replication competent virus. This paper used EIAV with Rabies envelope to produce integrating virus with retrograde transport capabilities.

EIAV-VEGF INJECTed into hindlimb results in elevated VEGF expression in spinal tissue- virus can induce VEGF in target tissue

point: RETROGRADE WORKS

delayed decrease in rotarod task in SOD1 mice
delayed disease onset
increased lifespan

35
Q

Paper: Lentiviral silencing of SOD1 by RNA

A

siRNA construct for SOD1 delays onset of disease in SOD1 mice

36
Q

Paper: AAV4-mediated expression IFG-1 and VEGF

A

AAV deliver IGF-1 or VEGF

ALS survive better when added.

prolonged survival/motor function in animals

Neurobiology of Disease (8 decks)

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