Brainscape's Knowledge GenomeTM

Browse over 1 million classes created by top students, professors, publishers, and experts.


See full index

ATU1 > Neurodegeneration > Flashcards

Neurodegeneration Flashcards

1
Q

What important biological role does tau have?

A

Stabilising microtubules through promoting microtubule polymerisation
Thereby AIDS neuronal structure and axon all transport

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
2
Q

On what residues is tau phosphorylated?

A

Serine and threonine residues

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
3
Q

What chromosome is MAPT found on?

A

Chromosome 17q21

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
4
Q

What effect does phosphorylation have on tau binding to MTs?

A

Negative regulation
Hyperphosphorylation impairs normal function of protein
Forms paired helical filaments

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
5
Q

Define paired helical filaments

A

Two twisting strands with an apparent periodicity of 80nm and an alternating width between 8 and 20nm

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
6
Q

What do paired helical filaments aggregate to?

A

Into soluble filamentous amyloid deposits in neuronal cell bodies/processes and glia - neurofibrillary tangles
This process either leads to neuronal dysfunction and death or is a marker of neuronal death

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
7
Q

What genetic factors increase tau dysfunction?

A

Tau mutations
APP, PS1 and PS2 mutations
Other mutations

This lead to the perturbation of 4R/3R ration
Loss of tau function
Gain of toxic function

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
8
Q

Describe pink inclusion bodies

A

Tau positive spherical cytoplasmic neuronal inclusions, composed of straight filaments

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
9
Q

Where are NFTs and neuritis threads found?

A

The gray matter of the frontal cortex
Particularly seen within AD
Filaments and tangles occurring inside the neuronal and cause the neuronal to die

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
10
Q

Where are peri nuclear inclusions found?

A

Within the frontal cortex

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
11
Q

In which diseases are neuronal tau positive inclusions found?

A 
AD
Corticobasal degeneration
Dementia pugilisitca
Progressive supra nuclear palsy
Picks disease
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
12
Q

Which mutated form of alpha synuclein colocalises with tau filaments?

A

A53T

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
13
Q

What other inclusions colocalise with tau filaments?

A

Huntingtin inclusions

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
14
Q

What is PET and what has it shown?

A

See a higher accumulation of tau and phosphorylated/accumulated forms of tau which correlates with the yellow marker (PIB) that binds onto the amyloid
PBB3 binds to tau

Positron emission tomography

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
15
Q

Which mutations impair tau protein function?

A

G272V
D280K
P301L/S

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
16
Q

Which mutations promote tau aggregation?

A

G272V
P301L/S
V337M

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
17
Q

What mutations alter exon 10 splicing?

A

N279K
D280K
L284L
S350N

Exon 10 splicing splits the variation from 3R to 4R tau - all the mutations have different outcomes in disease

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
18
Q

What is frontotemporal dementia?

A

A clinical group of neurodegenerative diseases

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
19
Q

What are the clinical features of FTD?

A

Mean age of onset is 55-65 years
Male are more prone than female
Prominent frontal lobe symptoms - personality changes
- loss of socially acceptable behaviour and emotions
- compulsive behaviour
- language dysfunction
- movement disorder

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
20
Q

What are the symptoms that you need three of?

A 
Early disinhibition
Early apathy, loss of motivation 
Loss of emotional recognition 
Perseveration, compulsive ritualistic behaviour
Hyperorality/ dietary changes
FTD neuropsychological profile
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
21
Q

Or what are the other symptoms required for diagnosis?

A

Frontal and or anterior temporal atrophy (other radiological findings)
Presence of a known mutation
And one symptom described from 1-6

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
22
Q

What percentage of dementia cases in the us are FTD syndromes?

A

10-15%

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
23
Q

Is FTD more or less common than AD below the age of 60?

A

More

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
24
Q

What is the FTD:AD ratio in those aged 45-65?

A

1:1

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
25
Q

What here networks are damaged in FTD within the frontal lobe?

A

Dorsolateral prefrontal cortex
Anterior cingulate cortex
Orbitiofrontal cortex

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
26
Q

What is a clinical feature of damage to the dorsolateral prefrontal cortex?

A

Working memory dysfunction

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
27
Q

What is a clinical feature of damage to the orbitofrontal cortex?

A

Behavioural disinhibition

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
28
Q

What is a clinical feature of damage to the anterior cingulate cortex?

A

Lack of motor and psychic initiative

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
29
Q

What are the two main subtypes of FTD?

A

1) tau positive inclusions present

2) absence of tau positive inclusions

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
30
Q

What are the FTD subtypes based on clinical presentation?

A 
Behaviour variant (60%) 
Semantic progressive primary aphasia
Nonfluent progressive primary aphasia (20%)
Progressive supra nuclear palsy 
Corticobasal syndrome
FTD with motor neuron disease (15%)
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
31
Q

Among individuals with FTD approximately how many have a single gene mutation?

A

10%

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
32
Q

What is the familial pattern of inheritance?

A

Approximately 20-40% of FTD patients have an affected 1st degree relative

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
33
Q

What did genetic linkage studies of FLTD reveal?

A

Loci of chromosomes 3p, 9, 9p and 17q

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
34
Q

What are the most prevalent genes in FLTD and where are they located?

A

Tau and progranulin - chromosome 17q21

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
35
Q

What is the autosomal dominant form of FLTD linked to chromosome 17q21 termed?

A

FTDP-17

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
36
Q

What is the pathological confirmation of clinical FTD?

A

1) histological diagnosed with neuronal loss and gliosis, spongiosis and ballooned neurones
2) abnormal protein inclusions in neurons and glial:
- tauopathies: FLTD with tau positive inclusions
- TDP-43 proteinopathies: FLTD with tau negative but with TDP-43 and ubiquitin positive inclusions
- FUS: FLTD with tau and TDP-43 negative but ubiquitin and fused in sarcoma inclusions

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
37
Q

What is TDP-43 encoded by?

A

TAR DNA binding protein

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
38
Q

Where is TARDP located?

A

Chromosome 1

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
39
Q

What are TARDP functions?

A

Transcriptional regulation
Exon splicing
mRNA stabilisation, hNFL
Neuronal activity responsive factor

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
40
Q

What TARDP substitution might be a risk factor for FTLD?

A

A90V

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
41
Q

How is TDP-43 presented in FLTD-U?

A

Hyper phosphorylated and ubiquinated

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
42
Q

What other disease is TFP-43 present in?

A

ALS

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
43
Q

Are TDP-43 inclusions amyloidogenic?

A

No

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
44
Q

What are the factors for TDP-43 mediated neurodegenerative?

A

Epigenetics
Environmental
Genetics: PGRN mutations etc

45
Q

What does aggregation and sequestration of TDP-43 lead to?

A

Dystrophic neuritis
Cytoplasmic inclusions
Intranuclear inclusions
- deregulation of transcription
- alterations in mRNA splicing or stability
- alterations in TDP-43 dependent signalling or trafficking

46
Q

What do the current drugs used do? FTD

A

Do not cure

Temporarily relieve some of the symptoms

47
Q

What are the three types of drug used for FTD?

A

Antipsychotics
Antidepressants
Nmda receptor antagonists

48
Q

What do antipsychotics do?

A

Block dopamine to alleviate behavioural symptoms
Quetiapine
Risperidone

49
Q

What do antidepressants do?

A

Replete the loss in serotonergic pathways

  • TCA
  • SSRI
50
Q

What do NMDA receptor antagonists do?

A

Ebixa

Act as an antagonist to glutamate gated ion channels

51
Q

What are the tau focusd drug designs?

A

Tau kinases - inhibit the phosphorylation of tau
Inhibitors of tau fibrillisation in NFTs
Microtubule stabilising agents

52
Q

Name tau kinases

A

Glycogen synthase kinase 3 beta

Cycling dependent kinase 5

53
Q

What inhibitors of tau fibrillisation are there?

A

Methylene blue

TRx

54
Q

What microtubule stabilising agents are there?

A

TPI 287

55
Q

What does TDP-43 focuses drug design concentrate on?

A

Inhibition of TDP-43 aggregation

56
Q

What is tau?

A

A microtubule associated protein largely localised to neuronal axons

57
Q

What does the variable expansion depend upon?

A

The disorder

58
Q

What does paternal transmission cause?

A

Increased repeat size

59
Q

What happens to repeat size from generation to generation?

A

Varies but an overall tendency for repeat length to increase

60
Q

What are the clinical features of TRD?

A

Almost all exhibit forms of ataxia
- chorea, dystonia, dysarthria, akathisia, seizure
Progressively degenerative
Variable age of onset from childhood to middle age
The larger the expansion the earlier the onset

61
Q

Describe type 1 triplet expansion

A 
Repeat always CAG
Pathological threshold = 35-40 
Always translated
Autosomal dominant
Neurodegenerative
Neuronal inclusions
62
Q

Describe type II

A 
Repat codon vaires
pathological threshold - 100+
Transcribed but not translated
Varied inheritance 
Variable, often pleiotropic phenotypes
No inclusions seen
63
Q

What type of triplet repeat disease is Huntingtons disease?

A

Type I

gene locus = 4-16.3

64
Q

Give an example of a type II repeat disease

A

FRAXA

Gene locus = Xq27.3

65
Q

What is the current suggested model for gene expansion in non-dividing cells?

A

Loop formation from single strand break repair

  1. Loop formed during base excision repair
  2. Three models for loop incorporation into duplex DNA involving mismatch repair (MMR) machinery
66
Q

Why is type II triplet repeats disorders more complicated?

A

Within regions thats aren’t replicating - type 2 expansions go very very high

67
Q

What was the previously suggested model for gene expansion in non dividing cells?

A

Previously though to be mainly through double strand break repaid by homologous recombination, crossover or non-homologous end joining

68
Q

What are the three models for loop incorporation?

A
  1. Dividing cells - incorporated in replication
  2. Non-dividing cells - active MSH2-MSH3 recruits canonical MMR
  3. MSH2-MSH3 recruits non-MMR machinery
    Result in loop incorporation
69
Q

Who first described Huntingtons disease?

A

George Huntington 1872

70
Q

What is the prevalence of hunting tons disease?

A

4-10/10000 and most heavily research trinucleotide repeat disorder to date

71
Q

What are the clinical features of hunting tons disease?

A

Initially minimal, patients can suppress or mask the irregular movements
Chorea occurs in 90% of cases
Additional components are cognitive decline
- Loss of memory, difficulty concentrating and judgement errors
Progresses to death within 15-20 years after onset mostly by respiratory failure but also infection and suicide

72
Q

Where does selective loss in Huntingtons disease occur?

A

Cerebral cortex and corpus striatum

73
Q

Where are the first altered neurotransmitters?

A

Medium sized spiny neurones containing GABA and enkephalin

74
Q

Disruption to what causes impaired communication to muscles?

A

Disrupted signalling from the thalamus and motor cortex

75
Q

Where is the huntingtons disease gene located to?

A

mapped to 4p16.3 locus

67 exons encoding a protein of 3144 amino acids

76
Q

Where is the underlying CAG mutation found?

A

Exon 1

77
Q

What is the major form of Huntingtons disease?

A

Autosomal dominant

- Some known sporadic cases

78
Q

What is the age of onset inversely related to?

A

The CAG repeat length

79
Q

What else does the gene contain?

A

WW domains and caspase cleavage sites

80
Q

Describe the protein huntington.

A

350 kDa
Unassigned function
Polyglutamine repeat is located near the N-terminus
Contains a number of HEAT-repeat motifs and a nuclear export signal

81
Q

Within the cell where is the wild type protein associated?

A

ER
Microtubules
Mitochondria
Synaptic vesicles

82
Q

In the brain where is the expression predominantly?

A

Neurones

83
Q

Where is mutated huntington known to form aggregates?

A

Cytoplasm and the nucleus

84
Q

How was it determined huntington was required during development?

A

KO mice die at 7.5 postnatal day

85
Q

What are the believed selected roles of huntington?

A
  1. intracellular trafficking and retrograde fast axonal transport
  2. Vesicle endocytosis and membrane recycling
  3. Transcription and histone acetylation
86
Q

What does PolyQ huntington inhibit?

A

Acetyltransferase activity and decreases levels of acetylated histones - HDAC inhibitors reverse this phenomena

87
Q

What are the steps in diagnosing hunting tons?

A

Clinical assessment: neurological testing, motor impersistence, family history
Neuroimaging: EEG, CT and MRI scans of the brain
Genetic screening: DNA based genetics testing to quantify CAG repeat length in the huntington gene
Prenatal diagnosis

88
Q

What is the current treatment for Huntingtons disease?

A

No cure
Movement disorder medication: tetrabenazine
Psychiatric disorder medication: tricyclic or SSRI
Haloperidol for psychosis and hallucinations
Phenothiazine for movements and anxiety
lithium for mood swings

89
Q

What do HDAC inhibitors do in treating Huntingtons disease?

A

Allow histones to wrap more tightly around DNA
Mutant huntington inhibits acetylation of histone H3 and H4
These agents can get across the BBB and work to counter the effect of mutant huntington
Selisistat - safe and tolerable in a phase II trial of HD

90
Q

What is multiple sclerosis?

A

A chronic autoimmune disorder that progressively robs sufferers of cognitive function and the ability to sense the world around them, and the capacity to walk

91
Q

What are the clinical features of MS?

A 
Vision problems 
Numbness
Difficulty walking
Fatigue
Depressing
Emotional changes
Coordination problems 
Balance problems
92
Q

How many people worldwide are affected by MS?

A

4000000

Women:men = 2:1

93
Q

What is the age of onset of MS?

A

18-50 years

94
Q

Where is MS more common?

A

Populations from northern latitudes with people moving to northern climes before 15 having a greater risk

95
Q

What is the difference in life expectancy of someone suffering from MS and a healthy person?

A

5-7 years shorter

96
Q

What are the types of MS?

A

Relapsing-Remitting (85%)
- attacks then partial or complete recovery
Secondary progressive
- Occasional relapses but symptoms remain constant
Primary progressive
- 10% - slow onset but continuos worsening condition
Progressive relapsing
- Rarest form - Steady worsening of condition at onset

97
Q

What is the criteria for diagnosing MS?

A
  1. Disease in different parts of the nervous system
  2. Signs of at least two separate false ups - occurring at least 30 days apart
    McDonals Diagnosis criteria for MS: definite diagnosis - clinically isolated syndrome with MRI findings
    Allows for early and accurate MS diagnosis
98
Q

What is the neuropathology characteristics of MS?

A
  • Inflammation
  • Multifocal areas of demyelination
  • Involves immune system and neurological system
  • Continual deposition of sclerotic plaques
99
Q

In MS where are plaques common?

A

White matter
Present in brain, brain stem, optic nerve and spinal cord
Lesions formed from infiltration of lymphocytes and macrocytes

100
Q

What does MRI enable detection of in MS?

A

Demyelinating lesions in MS brains and spinal cord

101
Q

When does most of the damage occur in MS?

A

Early on and decreases over time - although some destruction can be observed years and decades after

102
Q

What is the etiology of MS?

A

Pathogens - molecular mimicry, chemicals, dite
Genomic allelic variations: monozygotic twins 30%
LINKAGE AND ASSOCIATION SUTIDES
gENE REARRANGMENTS - SOMATIC MUTATIONS, RETROVIRAL AND Mrna SPLCIING

103
Q

What factors have been identified to influence MS?

A

Vitamin D deficiency
Infectious mononucleosis/Epstein Barr virus
Genetics

104
Q

What effects does vitamin D deficiency have?

A

Vitamin D3 receptor important in immune function
Present on T regulator cells
Vitamin D ans sunlight may slow MS

105
Q

What effect does infectious mononucleosis have?

A

99% of MS patients have EBV titres
EBV RNA transcripts found in inflammatory lesions
EBV stimulates toll 3 receptors to release pro inflammatory interferons

106
Q

What effects does genetics have on MS?

A

HLS DRB2 *1503 allele is a 2 fold risk factor
1L 2 receptor
IL 7 receptor
50 new candidates genes have been identified with low risk factors

107
Q

What are the main treatments used for MS?

A 
No cure
Relieving the symptoms:
Anti depressants laxatives anti-convulsants 
Slowing progression:
ABC treatments 
Chemotherapeutic agents 
Corticosteroids and ACTH
108
Q

What does ABC treatments stand for?

A 
Avon
Betaseron/Betaferon
Copaxone
Now also added - Rebif
Novantrone

ATU1 (3 decks)

Brainscape helps you reach your goals faster, through stronger study habits.
© 2024 Bold Learning Solutions. Terms and Conditions