Neurodegeneration Flashcards
What important biological role does tau have?
Stabilising microtubules through promoting microtubule polymerisation
Thereby AIDS neuronal structure and axon all transport
On what residues is tau phosphorylated?
Serine and threonine residues
What chromosome is MAPT found on?
Chromosome 17q21
What effect does phosphorylation have on tau binding to MTs?
Negative regulation
Hyperphosphorylation impairs normal function of protein
Forms paired helical filaments
Define paired helical filaments
Two twisting strands with an apparent periodicity of 80nm and an alternating width between 8 and 20nm
What do paired helical filaments aggregate to?
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
What genetic factors increase tau dysfunction?
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
Describe pink inclusion bodies
Tau positive spherical cytoplasmic neuronal inclusions, composed of straight filaments
Where are NFTs and neuritis threads found?
The gray matter of the frontal cortex
Particularly seen within AD
Filaments and tangles occurring inside the neuronal and cause the neuronal to die
Where are peri nuclear inclusions found?
Within the frontal cortex
In which diseases are neuronal tau positive inclusions found?
AD Corticobasal degeneration Dementia pugilisitca Progressive supra nuclear palsy Picks disease
Which mutated form of alpha synuclein colocalises with tau filaments?
A53T
What other inclusions colocalise with tau filaments?
Huntingtin inclusions
What is PET and what has it shown?
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
Which mutations impair tau protein function?
G272V
D280K
P301L/S
Which mutations promote tau aggregation?
G272V
P301L/S
V337M
What mutations alter exon 10 splicing?
N279K
D280K
L284L
S350N
Exon 10 splicing splits the variation from 3R to 4R tau - all the mutations have different outcomes in disease
What is frontotemporal dementia?
A clinical group of neurodegenerative diseases
What are the clinical features of FTD?
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
What are the symptoms that you need three of?
Early disinhibition Early apathy, loss of motivation Loss of emotional recognition Perseveration, compulsive ritualistic behaviour Hyperorality/ dietary changes FTD neuropsychological profile
Or what are the other symptoms required for diagnosis?
Frontal and or anterior temporal atrophy (other radiological findings)
Presence of a known mutation
And one symptom described from 1-6
What percentage of dementia cases in the us are FTD syndromes?
10-15%
Is FTD more or less common than AD below the age of 60?
More
What is the FTD:AD ratio in those aged 45-65?
1:1
What here networks are damaged in FTD within the frontal lobe?
Dorsolateral prefrontal cortex
Anterior cingulate cortex
Orbitiofrontal cortex
What is a clinical feature of damage to the dorsolateral prefrontal cortex?
Working memory dysfunction
What is a clinical feature of damage to the orbitofrontal cortex?
Behavioural disinhibition
What is a clinical feature of damage to the anterior cingulate cortex?
Lack of motor and psychic initiative
What are the two main subtypes of FTD?
1) tau positive inclusions present
2) absence of tau positive inclusions
What are the FTD subtypes based on clinical presentation?
Behaviour variant (60%) Semantic progressive primary aphasia Nonfluent progressive primary aphasia (20%) Progressive supra nuclear palsy Corticobasal syndrome FTD with motor neuron disease (15%)
Among individuals with FTD approximately how many have a single gene mutation?
10%
What is the familial pattern of inheritance?
Approximately 20-40% of FTD patients have an affected 1st degree relative
What did genetic linkage studies of FLTD reveal?
Loci of chromosomes 3p, 9, 9p and 17q
What are the most prevalent genes in FLTD and where are they located?
Tau and progranulin - chromosome 17q21
What is the autosomal dominant form of FLTD linked to chromosome 17q21 termed?
FTDP-17
What is the pathological confirmation of clinical FTD?
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
What is TDP-43 encoded by?
TAR DNA binding protein
Where is TARDP located?
Chromosome 1
What are TARDP functions?
Transcriptional regulation
Exon splicing
mRNA stabilisation, hNFL
Neuronal activity responsive factor
What TARDP substitution might be a risk factor for FTLD?
A90V
How is TDP-43 presented in FLTD-U?
Hyper phosphorylated and ubiquinated
What other disease is TFP-43 present in?
ALS
Are TDP-43 inclusions amyloidogenic?
No
What are the factors for TDP-43 mediated neurodegenerative?
Epigenetics
Environmental
Genetics: PGRN mutations etc
What does aggregation and sequestration of TDP-43 lead to?
Dystrophic neuritis
Cytoplasmic inclusions
Intranuclear inclusions
- deregulation of transcription
- alterations in mRNA splicing or stability
- alterations in TDP-43 dependent signalling or trafficking
What do the current drugs used do? FTD
Do not cure
Temporarily relieve some of the symptoms
What are the three types of drug used for FTD?
Antipsychotics
Antidepressants
Nmda receptor antagonists
What do antipsychotics do?
Block dopamine to alleviate behavioural symptoms
Quetiapine
Risperidone
What do antidepressants do?
Replete the loss in serotonergic pathways
- TCA
- SSRI
What do NMDA receptor antagonists do?
Ebixa
Act as an antagonist to glutamate gated ion channels
What are the tau focusd drug designs?
Tau kinases - inhibit the phosphorylation of tau
Inhibitors of tau fibrillisation in NFTs
Microtubule stabilising agents
Name tau kinases
Glycogen synthase kinase 3 beta
Cycling dependent kinase 5
What inhibitors of tau fibrillisation are there?
Methylene blue
TRx
What microtubule stabilising agents are there?
TPI 287
What does TDP-43 focuses drug design concentrate on?
Inhibition of TDP-43 aggregation
What is tau?
A microtubule associated protein largely localised to neuronal axons
What does the variable expansion depend upon?
The disorder
What does paternal transmission cause?
Increased repeat size
What happens to repeat size from generation to generation?
Varies but an overall tendency for repeat length to increase
What are the clinical features of TRD?
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
Describe type 1 triplet expansion
Repeat always CAG Pathological threshold = 35-40 Always translated Autosomal dominant Neurodegenerative Neuronal inclusions
Describe type II
Repat codon vaires pathological threshold - 100+ Transcribed but not translated Varied inheritance Variable, often pleiotropic phenotypes No inclusions seen
What type of triplet repeat disease is Huntingtons disease?
Type I
gene locus = 4-16.3
Give an example of a type II repeat disease
FRAXA
Gene locus = Xq27.3
What is the current suggested model for gene expansion in non-dividing cells?
Loop formation from single strand break repair
- Loop formed during base excision repair
- Three models for loop incorporation into duplex DNA involving mismatch repair (MMR) machinery
Why is type II triplet repeats disorders more complicated?
Within regions thats aren’t replicating - type 2 expansions go very very high
What was the previously suggested model for gene expansion in non dividing cells?
Previously though to be mainly through double strand break repaid by homologous recombination, crossover or non-homologous end joining
What are the three models for loop incorporation?
- Dividing cells - incorporated in replication
- Non-dividing cells - active MSH2-MSH3 recruits canonical MMR
- MSH2-MSH3 recruits non-MMR machinery
Result in loop incorporation
Who first described Huntingtons disease?
George Huntington 1872
What is the prevalence of hunting tons disease?
4-10/10000 and most heavily research trinucleotide repeat disorder to date
What are the clinical features of hunting tons disease?
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
Where does selective loss in Huntingtons disease occur?
Cerebral cortex and corpus striatum
Where are the first altered neurotransmitters?
Medium sized spiny neurones containing GABA and enkephalin
Disruption to what causes impaired communication to muscles?
Disrupted signalling from the thalamus and motor cortex
Where is the huntingtons disease gene located to?
mapped to 4p16.3 locus
67 exons encoding a protein of 3144 amino acids
Where is the underlying CAG mutation found?
Exon 1
What is the major form of Huntingtons disease?
Autosomal dominant
- Some known sporadic cases
What is the age of onset inversely related to?
The CAG repeat length
What else does the gene contain?
WW domains and caspase cleavage sites
Describe the protein huntington.
350 kDa
Unassigned function
Polyglutamine repeat is located near the N-terminus
Contains a number of HEAT-repeat motifs and a nuclear export signal
Within the cell where is the wild type protein associated?
ER
Microtubules
Mitochondria
Synaptic vesicles
In the brain where is the expression predominantly?
Neurones
Where is mutated huntington known to form aggregates?
Cytoplasm and the nucleus
How was it determined huntington was required during development?
KO mice die at 7.5 postnatal day
What are the believed selected roles of huntington?
- intracellular trafficking and retrograde fast axonal transport
- Vesicle endocytosis and membrane recycling
- Transcription and histone acetylation
What does PolyQ huntington inhibit?
Acetyltransferase activity and decreases levels of acetylated histones - HDAC inhibitors reverse this phenomena
What are the steps in diagnosing hunting tons?
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
What is the current treatment for Huntingtons disease?
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
What do HDAC inhibitors do in treating Huntingtons disease?
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
What is multiple sclerosis?
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
What are the clinical features of MS?
Vision problems Numbness Difficulty walking Fatigue Depressing Emotional changes Coordination problems Balance problems
How many people worldwide are affected by MS?
4000000
Women:men = 2:1
What is the age of onset of MS?
18-50 years
Where is MS more common?
Populations from northern latitudes with people moving to northern climes before 15 having a greater risk
What is the difference in life expectancy of someone suffering from MS and a healthy person?
5-7 years shorter
What are the types of MS?
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
What is the criteria for diagnosing MS?
- Disease in different parts of the nervous system
- 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
What is the neuropathology characteristics of MS?
- Inflammation
- Multifocal areas of demyelination
- Involves immune system and neurological system
- Continual deposition of sclerotic plaques
In MS where are plaques common?
White matter
Present in brain, brain stem, optic nerve and spinal cord
Lesions formed from infiltration of lymphocytes and macrocytes
What does MRI enable detection of in MS?
Demyelinating lesions in MS brains and spinal cord
When does most of the damage occur in MS?
Early on and decreases over time - although some destruction can be observed years and decades after
What is the etiology of MS?
Pathogens - molecular mimicry, chemicals, dite
Genomic allelic variations: monozygotic twins 30%
LINKAGE AND ASSOCIATION SUTIDES
gENE REARRANGMENTS - SOMATIC MUTATIONS, RETROVIRAL AND Mrna SPLCIING
What factors have been identified to influence MS?
Vitamin D deficiency
Infectious mononucleosis/Epstein Barr virus
Genetics
What effects does vitamin D deficiency have?
Vitamin D3 receptor important in immune function
Present on T regulator cells
Vitamin D ans sunlight may slow MS
What effect does infectious mononucleosis have?
99% of MS patients have EBV titres
EBV RNA transcripts found in inflammatory lesions
EBV stimulates toll 3 receptors to release pro inflammatory interferons
What effects does genetics have on MS?
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
What are the main treatments used for MS?
No cure Relieving the symptoms: Anti depressants laxatives anti-convulsants Slowing progression: ABC treatments Chemotherapeutic agents Corticosteroids and ACTH
What does ABC treatments stand for?
Avon Betaseron/Betaferon Copaxone Now also added - Rebif Novantrone
