Parkinson's Disease Flashcards
Huntingon’s Disease + Symptoms
Degeneration of MSNs = predominantly indirect MSNs
- See loss of enkephalin staining
Cognitive, motor, psychiatric
- Motor = dystonia, chorea, difficulty with speech/swallowing
- Psychiatric = apathy, dysphoria, anxiety
- Cognitive = lack of cognitive flexibility, slowness of thought, mild cognitive impairment
HD - Genetics
Chromosome 4 - Huntingtin gene
Autosomal dominant
Polyglutamine repeats - CAG
10-35 = normal
36+ = PD
The more repeats, the earlier the onset, the more severe the disease
Intracellular aggregates called INCLUSION BODIES - axons and dendrites of MSNs degenerate (mainly indirect MSNs)
Parkinson’s Disease + Symptoms
Neurodegeneration of substantia nigra pars compacta (SNc) neurones
Symptoms - bradykinesia, loss of smell, shuffling gait, resting tremor, rigidity, dystonia
PD - Genetics
GWAS - identified SNP (single nucleotide polymorphisms)
High risk; mutation causes EOPD (autosomal recessive) = PINK1 - kinase involved in mitochondria protection; cause mitochondrial dysfunction in SNc neurones
SNCA (encodes a-synuclein) - <30 mutations have been found to cause EOPD; important role in maintaining an adequate supply of synaptic vesicles in presynaptic terminals
Medium risk = GBA - encodes an active enzyme in lysosomes, involved in protein degradation
Why are SNc neurones vulnerable?
- Selective vulnerability
2. Prion-like spread hypothesis
Why are SNc neurones vulnerable?
Selective vulnerability
High energetic load: SNc neurones ~ 100-200,000 synapses = huge axonal arborisations
Increased cellular demand:
- Increased mitochondrial function to maintain ionic gradients (PINK1)
- Increased protein turnover + degradation (GBA)
- Increased synaptic transmission (SNCA)
SNc neurones are vulnerable whereas VTA neurones are not
- SNc = projects to the dorsal striatum (movement)
- VTA = projects to the ventral striatum (motivation)
- SNc uses L-type Ca channels for pacemaking
High levels of ATP (mitochondria; PINK1) are required to maintain Ca balance –> mitochondrial stress - VTA uses a persistent Na+ current for its pacemaking activity, and they express Ca buffers (ie. calbindin)
***LINK = Nimidopine (L-type Ca channel antagonist) - novel therapeutic treatment in PD
Braak stages
Braak’s hypothesis = sporadic PD is caused by an infective pathogen which enters the body via the nasal cavity, is swallowed and reaches the gut; the nose and digestive tract therefore have LB pathology
Braak stages = a staging system describing the spread of LB pathology (LBP) from the PNS to the CNS
BUT - not all PD Ps follow the staging system!
1 + 2 = LBP brainstem - autonomic + olfactory disturbances
3 + 4 = LBP midbrain/some cortical - sleep + motor disturbances
5 + 6 = LBP more cortical - emotional + cognitive disturbances
Why are SNc neurones vulnerable?
Prion-like spread hypothesis
FOR
Braak’s hypothesis = a pathogenic agent infects the brain via the nose or the gut
- Embryonic stem cells implanted into PD brains to try and restore behavioural abnormalities = stem cells developed LB inclusions
- Inject fibrils into the striatum of mice - healthy neurones form LB
BUT need endogenous synuclein; a-synuclein K/O mice = inject fibrils, do not form LB in healthy neurones
(Explains selective vulnerability hypothesis - neurones need to contain endogenous synuclein) - Human LB can cause neurodegeneration in mice
Inject human LB from dead PD P into SNc rat
Control = strong signals from DAergic neurones
4 weeks = not much change
4 months = reduced signal within striatum, few DAergic neurones
17 months = reduced signal within striatum (PET), most DAergic neurones have died (L-DOPA staining) - Perfomed similar experiments with monkeys = injection of human LBs also causes reduced signalling within the striatum + DAergic neuronal degeneration
- Injected synuclein fibrils into the upper intestine which is innervated by dorsal motor vagal neurones - found in LBs in these neurones
BUT did not find LW in the DAergic neurones which they vagal neurones innervate
THEREFORE - no proof of spreading (jumping synapses)
Why? - Maybe did not leave long enough
- Maybe the form of synuclein was incorrect (protein aggregates are very heterogeneous)
Why are SNc neurones vulnerable?
Prion-like spread hypothesis
AGAINST
Aggregates are not found in the expected regions (based on connectivity)
If spreading - expect to see LB in axonally linked regions
BUT - not all neurones express synuclein (must have endogenous synuclein to convert to LB)
AND
Cell vulnerability
- Host co-factors = assemblies of synthetic a-synuclein have been shown to have comparatively weak seeding capacities to seeds derived from the brain; the in vivo seeding efficacy of synthetic seeds is enhanced if the seed is aggregated on ex vivo tissue slices in culture
There is a poor correlation between disease duration and Braak stage
Rate Model: FOR
Can explain HD + PD
Optogenetically stimulated direct/indirect pathway
Cre down-stream of D1 (direct) or D2 (indirect)
Function ChR2-YFP expressed only in cells expressing Cre
PD = Activate indirect (D2)
- decrease in ambulatory time + decrease in fine movements
- increase in freezing time
- fine movements = less vigorous
HD = Activate direct (D1)
- increase in ambulatory time + increase in fine movements
- decrease in freezing time
- fine movements = more vigorous
PD - 2 novel mechanisms secondarily contributing to the stratal imbalance
Extra reading paper
No change in the spiking patterns of feed-forward interneurones (FFI)
- Role = enhance responsiveness to striatopallidal (indirect) neurones to cortical stimulation + decrease responsiveness of striatonigral (direct)
Therefore also weakens direct!
- Corticostriatal neurones preferentially innervate direct/indirect neurones DAergic lesion (6-ODHA) imbalances the activities -favoured innervation of indirect neurones!
HD - extra reading paper
Striatum = composed of striosomes (limbic innervates) + matrix (sensorimotor + associative cortical innervation)
Post-mortem = looked at the compartmental pattern of stratal abnormality
Clinical retrospective analysis = interviews to family
Striosome-matrix loss = continuum (controversial - some reported pure striosomal/matrix)
Striosomal loss =
- Lower mean CAG
- Later mean onset + later age of death (disease duration did not differ)
- Sig. higher mood dysfunction values
BUT - no correlation between matrix loss + motor symptoms
Maybe because matrix is very heterogenous!
Therefore - predominantly striosomal-death HD Ps could represent a sub-group of HD!!!
Study reports previous studies finding no correlation between CAG length + symptoms sub-type!
Rate Model: AGAINST 1
Timings 1
Cui
Rate model assumptions:
Direct pathway firing facilitated movement - ‘pro-kinetic’
Indirect pathway firing facilitated no movement - ‘anti-kinetic’
Cre-dependent viral expression of GCaMP (genetically encoded Ca indictor) = injected into the dorsal striatum in D1-Cre of A2-Cre mice
In vivo photometry using TCSPC (time correlated single photon counting) using deep-brain inserted fibre optics
Measured GCaMP while mice performed a motor task = lever-pressing operant task
Produced time-locked transients!
BOTH firing during active states and were quite during inactivate states = co-activated
BOTH peak phasic firing occurred just prior to the onset of movement
Another study found that optical activation of the indirect pathway decreases locomotion + that disrupting the pathway increased locomotion;
Does not necessarily contradict:
Direct pathway = promotes the activation of wanted motor programs
Indirect pathway = inhibition of unwanted motor programs
Rate Model: AGAINST 1
Timings 2
Klaus - studied the spatiotemporal organisation of the direct + indirect pathway MSNs during motor actions
Recorded IC [Ca] transients = an indirect measurement of neural activity
MSNs form functional groups/clusters - the degree of overlap of different MSN cluster firing represents the similarity/dissimilarities between behaviours
- More similar = closer ensembles
- More dissimilar = more distant ensembles
Striatal activity is therefore related to its representation in action space!
Explains reinforcement learning = learn to retrieve similar MSN ensembles (= action)
*** LINK:SCB = the spatiotemporal encoding also seen in dendritic spines = repetitive motor learning induces the coordinated formation of clustered dendritic spines in vivo - the pattern of new spine formation dependent on the pattern of task performance
Rate Model: AGAINST 1
Timings = Solution
SURROUND INHIBITION = aid the selective execution of desired movements by inhibiting undesired motor programs
Indirect = inhibits unwonted, related (competing) movements - provides blanket inhibition (inhibition of all motor programs) Direct = provides the release of inhibition for a specific motor program
Co-activation during movement = facilitates appropriate motor programs and inhibits competing motor programs
Optogenetically stimulate direct/indirect MSNs:
PD = activate all direct MSNs - weird, jerky movements (chorea) due to the activation of antagonistic muscles
HD = activate all indirect MSNs - all movements inhibited - bradykinesia
Rate Model: AGAINST 2
The model does not account for all the anatomical projections - it is too simplified!
ie. Hyperdirect pathway = corticosubthalamopallidal pathway (cortex –> STN)
CGaMP Ca transient imaging showed a dip in both direct and indirect pathway activity prior to movement - what was inhibiting the unwanted motor programs?
Solution = CENTRE-SURROUND MODEL Hyperdirect = a corollary signal is transmitted from the motor cortex --> STN to activate the GPi/SNr extensively = inhibition of both the selected, wanted motor programs and the unwanted motor programs
Direct = a corollary signal via the direct pathway to disinhibit target neurones involved in the selected motor programs
Indirect = a corollary signal via the indirect pathway to inhibit the other neurones involved in the competing, unwanted motor programs
Rate Model: AGAINST 3
Not all predictions of the model are observed
ie. Lesion GPi/SNr (output)
Expect = increased activation of the thalamus; HD-like chorea movements
BUT -
Reduces vigor = the speed + extent of the movement (gain; ‘volume’) was reduced
Rate Model: AGAINST 3
Solution =
Alternative function of basal ganglia
Basal ganglia might MODULATE VIGOR
Vigor = the ability to execute the movement components of a motor skill over a range of speeds, amplitudes and frequencies; vigor varies with motivation
ie. Motivated = increased speed/frequency/amplitude of action
Output = modulates vigor (inhibit output = reduce vigor)
Evidence:
- Optogenetically active direct (increased output) = more vigorous, fine movements
- Optogenetically active indirect (decreased output) = less vigorous, fine movements
BG responses occur later than the cortex, after the 1st muscle activity - inconsistent with the idea that the BG selects actions
Explains why PD Ps can move as fast as healthy Ps with the correct stimulus
ie. Severe PD patient on a bike
PD Treatments
Only symptomatic!!
Motor = Tetrabenezine - reduce chorea
- reversibly inhibits VMAT2 (Reserpine PD model)
- smaller RRP of DAergic vesicles
- can worsen psychiatric symptoms (monoamine theory of depression)
Cognitive = anti-depressants
Psychiatric = Lithium (GSK3 inhibitor)
PD Treatments
Symptomatic!!
Dopamine replacement = L-DOPA (precursor)
- Precursor crosses BBB (dopamine doesn’t)
- Serotoninergic neurones have DOPA decarboxylase = :-DOPA hijacks, produces a dopamine pump in the striatum
BUT - reduced effectiveness over time = therapeutic window decreases due to the eventual onset of dyskinesias
Theory - VMAT2 dysfunction has been identified in PD Ps
-target VMAT2 (increase or enhance function) = could extend the therapeutic window of L-DOPA (improve efficiency of DAergic packaging into vesicles)
VMAT2 is a drug target = enhance number of DAergic vesicles
Nimidopine (DHP) = L-type Ca channel blocker
- SNc neurones are vulnerable due to L-type Ca channels - therefore a potential therapeutic agent to utilise!!!
DBS
Treatment for PD
Stimulating electrode acts as a pacemaker
Common target STN - paradoxical (according to the Rate Model = should inhibit movement)
Could be due to PATTERNS of activity - different patterns of activity could be bad
Lacking evidence to show that oscillations are necessary to produce PD movements (causal)
BUT - a variety of abnormalities in patterned activities improve following L-DOPA treatment + DBS
Expensive ~ £30,000 - weigh up justifications!
Therapies to stop/slow/reverse PD
ABs to prevent a-synuclein aggregation
ie. BAN2401 (amyloid AB) = reliant on endogenous clearance mechanisms
Stem cell therapy - DAergic neurones
VMAT2 = enhance function or increase protein
L-type Ca channel blockers - Nimidopine
Given to people with AF (decrease SK activation which increases HR) = also less likely to develop PD
Glial-derived nerve growth factor - trial in Bristol
-results = not promising (no difference to control)
Maybe due to:
- Higher dose of GDNF could have been more effective
- Ps at an earlier stage of the condition may have responded better
Rate Model: AGAINST 3
Lesioning the GPi/SNr (output) is therapeutic in both hypokinetic-PD and hyperkinetic-HD disorders
May be that there are some shared rather than opposing circuit mechanisms
Not surprising due to the overlap of some symptoms
ie. Dystonia
