Huntingtons and Parkinsons Flashcards
How many people are affected by huntington’s
rare inherited neurological disorder affecting 10 in 100,000 people of western european descent and 0.1 in 100,000 people of asian and adrican descent
how is huntington’s inherited
- autosomal dominant - only need one copy
- one in two chance of inheriting from an affected parent
huntington’s symptoms
- chorea: uncoordinated movements, orolingual chorea, mental abilities and aspects of personality
- onset is usually 40s/50s
- no sudden loss of abilities but a progression
- physical symptoms are noticed first but anectotally loved ones of people with huntingtons notice cognitive symptoms first
how is huntington’s and death associated?
- people live for 15-20 years after initial onset
- death caused due to associated complications
- pneumonia (1/3), heart failure, choking, nutritional deficiency
- suicide is an associated risk (4x higher than general population)
huntington’s aetiology
- abnormal Hit gene on chromosome 4
- gene encodes for abnormal Hit protein - polyglutamine gene
- it encodes for >36 CAG repeats
- > 39 is pathogenic
- when 36-38 some may develop HD and some may not
- probably gain of function but unknown
- may interfere with regular Htt function
neuroanatomy of huntington’s
- degerantion of neuronal cells in frontal lobes and cauduate nucleus (striatum) of basal ganglia
- associated neuronal degeneration in temporal and frontal lobes in cerebral cortex –> reponsbible for higher order mental functioning, movements and sensations
- affect medium spiny neurons in striatum
- they receive DA from midbrain and release GABA
- this inhiits release of NT from other nerve cells
loss of medium spiny neurons –> loss of GABA secretion –> decreases inhibition of thalamus –> thalamus increases output to cerebral cortex –> disorganized and excessive movemnt patterns of chorea
pharmacotherapy for parkinsons
motor chorea
- olanzepine (D2 blocker)
- tetrabenazine (dopamine depleting agent)
- banzodiazepines
- resperidone
- sulpiride
- amantadine
cognitive
- none that enhance cognition
- modafinil targets DAA
- cholinesterase inhibitors
psychiatric
- depression: SSRIs, TCAs
- psychotic behaviour: atypical neuroleptics/antipsychotics
- mood swings: sodium valproate –> side effect is weight gain which is benedicial
future therapies
drugs slowing disease progression
- coenzyme Q - trend to slow disease
- riluzole - no major effect
- creatine - no major effect
- monocycline
transplants to repair cell damahe
- cell implants, stem cells (mixed resulst)
L-DOPA/levodopa
- intermediate in dopamine biosynthesis
- prodrug to increase DA levels in PD
- it can cross the BBB via active transport into presynaptic neurone and DA itself cannot
- when levodopa crosses BBB it metabolized to DA by AAD (aromatic L amino decarboxylase) –> bypasses the rate limiting step of TH
- excess precursor increases dopaminergic output
- helps for straight posture and regular gait
cardidopa and denserazide
- peripheral dopa decarboxylase inhibitors
- prevent the metabolism of L-DOPA to DA in the periphery which could lead to hypotension and arrhythmia
- when cardidop and L-dopa are combined there is more L-dopa transferring through BBB and a lower dose is required
neuroprotective factor of selegiline
- MAOI
- prevents nitrolysation of GAPDH which prevents cell death
- when GAPDG is nitrosylated it can enter the nucleus and cause cell death by associating with mutated Htt and through degradation of N-Cor protein
parkinson’s disease
- neurological disorder affecting chatecolamiine system in CNS
- degeneration of DA neurone projecting from SN to striatum
- this leads to DA depletion and loss of DA neurochemical markers –> DAT and VMAT2
- less DAT is seen in caudate nucleus
- presence of Lewy bodies: inclusions in cytoplasm of neurons formed by deposits of alpha-synuclein and ubiquitin
- manifests as muscle rigidity, resting tremor, bradykinesia and akinesia, gait step smaller, freezing in the moment
parkinson’s aetiology
- most cases are idiopathic
- genetic causes account for 5-10% of PD cases
- genetic causes have been assigned to different loci: PARK 1-19 which cause or increase risk of PD
- mutations in alpha-synuclein (PARK 1/4) - autosomal dominant, Parkin (PARK 2) - recessive , DJ-1 (PARK 7)
- variants in LRRK2 and SNCA cause PD –> causal and rare
- exposures: insecticides increase risk, MPTP induced PD (toxins that kill DA neurone)
- in us 1-1.5 million patients
- higher risk in men than women
- biggest risk is age (onset is usually 60)
Parkinson’s genetic component key points
- there is a genetic component
- genes have been identified to be causal: SNCA and LRRK2
- some causes are autosomal dominant or recessive
MPPP –> MPTP –> MPP+ mechanism
- MPTP byproduct of MPPP synthesis that induces PD
- MPPP is a synthetic opioid and is an analog of demerol
- MTPT crosses the BBB and is converted to toxic metabolite MPP+ by MAO-B in glial cells
- MPP+ is selectively taken up by DAT and accumulates in DA neurons –> neuron expressing high DA are most susceptible
- MPP+ induces Parkinsonism by inhibiting complex 1 in the electron transport chain in the mitochondria which causes oxidative stress and can causes loss of DA neurons
- VMAT2 can take up MPP+ in the cell into vesicles so it can’t act on the mitochondria
- since VMAT2 modulates the toxicity of MPP+, cells with high VMAT2 are more protected
Deprenyl
- MAO-B inhibitor prevents the conversion of MPTP to MPP+ in the cell
GBR 12909
- blocks DAT transport of MPP+ into the cell
how is tyrosine converted to DA
- tyrosine converted to dopa by tyrosine hydroxylase (rate limiting step)
- dopa converted to dopamine by dopa decarboxylase or amino acid decarboxylase (rapid conversion)
When does levopoda become inadequate?
- one to three years after disease progression mono therapy is inadequate
L DOPA adverse drug reaction
early
- hypotension
- nausea
- GI bleeding
- disturbed respiration
- hair loss
- arrhythmia
late
- psychiatric
confusion
extreme emotional states
vivid dreams
L-DOPA induced dyskinesia
L DOPA induced dyskenisea and how is it helped?
- after long term use people develop irregular movements
- patients with motor fluctuations on levodopa can benefit from addition of DA agonist to smooth motor fluctuations and improve symptoms
Why don’t we have a good genetic animal model for motor impairments in PD?
- rodents may be more resistant to dopamine loss
- may have evolved this way because mice with dopamine loss that can’t run away die
- you can decrease DA neurons in mice by 90-95% and they are still able to walk
- can’t decrease DA neurons by 100% because it can’t walk but also can’t move around to eat and survive
- the only way to study 100% DA neuron killing are through unilateral killing
normal neurotransmission vs lack of DA transporter
- DA in EC space is 6x higher when DAT is knocked out because there is no way to recycle DA
- this reduces DA stores in vesicles by 90%
- all DA that is available is coming from synthesis by TH
- if TH is inhibited then DA release is inhibited
DAT-KO mice as a PD model
- what effect does aMT have on DA levels and behaviour
- what are the effects of L DOPA and MDMA
DA levels
- aMT blocks TH which induces severe DA depletion in the striatum of DAT-KO mice
- when aMT is administered there is a decrease in DA in striatal tissue of WT mice and none in DAT-KO mice because there are no vesicle stores of DA, and there is no decrease in striatal EC DA in WT and but it goes down to 0 after an hour in DAT-KO mice because there is nothing left to release from vesicles
behaviour
- DAT-KO mice after aMT administration: the animals can’t initiate movement
- locomotion at 0, low number of steps, high catalepsy (freezing), long time grasping on rod
LDOPA
- restored locomotor activity in DAT-KO mice after aMT was administered
- LDOPA/CD also had a good response and needed less DA to have an effect
- there was very little response to DA receptor agonists
- this may be because DA receptor agonists stimulate system constantly while L-DOPA stimulates in pulses
MDMA
- high doses restored locomotor activity
- but MDMA is not transformed into DA
- MDMA seems to be able to increase locomotor activity independent of DA system
