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
