Lecture 23 Flashcards
Parkinson’s Disease (PD) is characterised by severe loss of _______ _______ _______ neurons in the _______
Parkinson’s Disease (PD) is characterised by severe loss of substantia nigra dopaminergic neurons in the midbrain
__-__% of the substantia nigra dopaminergic are lost by the time a patient presents with clinical symptoms
60-70% of the substantia nigra dopaminergic are lost by the time a patient presents with clinical symptoms
What are the normal funcions of the Substantia nigra (SN)/
control voluntary movement
produces the neurotransmitter dopamine
(dopamine regulates mood)
The neuromelanin gives the dark pigmented colour of the SN. which part of the SN are they in?
Pars compacta
It is the projections from pars compacta to the _____ that are affected in PD
It is the projections from pars compacta to the striatum that are affected in PD
What is the role of the striatum
planning and modulation of movement pathways
Neuronal loss mainly occurs in whcih region of the SN?
ventrolateral (anterolateral) area - the region that projects to the striatum
The major form of parkinson’s disease is?
sporadic
what are some proposed mediators for sporadic PD?
toxins such as pesticides
metals
drugs MPTP
true or false
Inherited PD can be both autosomal dominant or recessive
true
Which genes of been identified as PD causing
alpha-synuclein (SNCA) Parkin (PRKN) Leucine-rich repeat kinase DJ-I PINK I
True or False
lewy bodies (apthology) can occur in the absense of any neuronal loss
true
What are Lewy bodies?
Lewy bodies are abnormal aggregates of protein that develop inside nerve cells in Parkinson’s disease (PD),
a-synuclein is…
the main protein component of Lewy bodies - it is natively unfolded
linked to learning or development of synaptic plasticity
Go through the Braak staing of Lewy body pathology in PD:
Stage 1: dorsal motor nucleus of the vaga nerve: ant. ______ structures
stage 2: lower rapha nuclei: locus coeruleus (located in brain stem) - control responses to ____ and ____ )
Stage 3: Substantia nigra, _____, parts of basal ______- clinical diagnosis
stage 4: temporal _______
Stage 5: temporal ______
Stage: neocortex - primary ____ and ______areas
Stage 1: dorsal motor nucleus of the vaga nerve: ant. olfactory structures
stage 2: lower rapha nuclei: locus coeruleus (located in brain stem) - control responses to stress and panic)
Stage 3: Substantia nigra, amygdala, parts of basal ganglia - clinical diagnosis
stage 4: temporal mesocortex
Stage 5: temporal neocortex
Stage: neocortex - primary sensor and motor areas
Somewhere along the a-syn folding /aggregation pathway a ___ species is thought to be generated
toxic species
______ can inhibit aggregation of a-synuclein
Dopamine
exposure to which factors can promote aggregation of a-synuclein?
iron
oxidants
nitration
exposure to environmental toxins
Dopamine induced a-synuclein oligomers are not ______ T reactive
thioflavin T reactive (widely used to visualize and quantify the presence of misfolded protein aggregates called amyloid,)
the presence of dopamine can change the aggregation properties of a-synuclein in they are..
resistant soluble oligomers (because the methoinine is oxidises)
There are 3 point mutations of the a-synuclein gene that can cause overexpression (triplication and duplication of gene)
What are they and how are they inherited?
A30P
A53T
E46K
Autosomal dominant inherited
An ____ in a-synuclein gene dosage leads to increased levels of a-synuclein = more aggregation
increase
transgenic mice expressing wild type a-synuclein have redced striatal ______ ______(involved in synthesis of dopamine) levels
transgenic mice expressing wild type a-synuclein have redced striatal tyrosine hydroxylase (involved in synthesis of dopamine) levels
There are _ different secretory pathways to release a-synuclein
3
Activation of ______ and ______ by a-synuclein are means to explain the inflammation associated with PD
activation of astrocytes and microglia by a-synuclein are means to explain the inflammation associated with PD
The propagation of a-synuclein can also…
reduce lifespan (in injected m83 mice), particularly when injected at birth
Which pathological aggregates are associated with a-synuclein, and what inheritance is it?
a-synuclein (dominant) - lewy bodies
explain the Parkin gene’s impact on PD
second most common one
Parkin (recessive) - substantia nigra degeneration occasioanlly Lewy bodies,
onset 10-50 yrs
Loss of function - recessive
If you lose parkin function you get non-ubiquitinated substances accumualting in neurons (“parkinG”)
- inihibits proteasomes
- includes a-synuclein among other proteins
explain the PINK1 gene’s impact on PD
PINK1 (recessive) - Lewy bodies, 30-50 yrs onset
Mitochondrial targetting sequence (normally targets TRAP1, mutation stops it from phosphorylating). If it can’t phosphorylate TRAP-1 there is less of a response to oxidative stress
Explain the DJ-1 gene’s impact on PD
DJ-1 (recessive) - no path found, onset 20-40 yrs
Normally involved in oxidative stress response and mitochondrial function
Explain the ATP13A2 gene’s impact on PD
ATP13A2 (recessive), Lewy bodies, young onset
Explain the LRRK2 gene’s impact on PD
most common ______ inherited cause of familial PD
LRRK2 (Dominant - most common), usually Lewy bodies
onset 30-50 yrs
Mutations increase kinase activity
LRRK2 also promotes mitochondrial and golgi fragmentation
The GBA enzyme mutation pathway to diease onset involves the formation of excess glucoserebioside from a lack of progression to _______
What does glucoserebioside do to help progress PD?
ceramide
glucoserebioside stabilises the a-synuclein oligomers
parkin mutation inhibits ______, meaning more oligomers are preset
proteasomes
LRRK2 can cause ____ fragmentation
Golgi fragmentation, results in increase formation of a-syn oligomers
PINK1, DJ-1 and Parkin seem to prevent the fragmentation of ______ normally
mitochondria
therefore loss of function of these result in less function mitochondria
