Lecture 23

Question 1

Parkinson’s Disease (PD) is characterised by severe loss of _______ _______ _______ neurons in the _______

Answer 1

Parkinson’s Disease (PD) is characterised by severe loss of substantia nigra dopaminergic neurons in the midbrain

Question 2

__-__% of the substantia nigra dopaminergic are lost by the time a patient presents with clinical symptoms

Answer 2

60-70% of the substantia nigra dopaminergic are lost by the time a patient presents with clinical symptoms

Question 3

What are the normal funcions of the Substantia nigra (SN)/

Answer 3

control voluntary movement
produces the neurotransmitter dopamine
(dopamine regulates mood)

Question 4

The neuromelanin gives the dark pigmented colour of the SN. which part of the SN are they in?

Answer 4

Pars compacta

Question 5

It is the projections from pars compacta to the _____ that are affected in PD

Answer 5

It is the projections from pars compacta to the striatum that are affected in PD

Question 6

What is the role of the striatum

Answer 6

planning and modulation of movement pathways

Question 7

Neuronal loss mainly occurs in whcih region of the SN?

Answer 7

ventrolateral (anterolateral) area - the region that projects to the striatum

Question 8

The major form of parkinson’s disease is?

Answer 8

sporadic

Question 9

what are some proposed mediators for sporadic PD?

Answer 9

toxins such as pesticides
metals
drugs MPTP

Question 10

true or false

Inherited PD can be both autosomal dominant or recessive

Answer 10

true

Question 11

Which genes of been identified as PD causing

Answer 11

alpha-synuclein (SNCA)
Parkin (PRKN)
Leucine-rich repeat kinase
DJ-I
PINK I

Question 12

True or False

lewy bodies (apthology) can occur in the absense of any neuronal loss

Answer 12

true

Question 13

What are Lewy bodies?

Answer 13

Lewy bodies are abnormal aggregates of protein that develop inside nerve cells in Parkinson’s disease (PD),

Question 14

a-synuclein is…

Answer 14

the main protein component of Lewy bodies - it is natively unfolded

linked to learning or development of synaptic plasticity

Question 15

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

Answer 15

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

Question 16

Somewhere along the a-syn folding /aggregation pathway a ___ species is thought to be generated

Answer 16

toxic species

Question 17

______ can inhibit aggregation of a-synuclein

Answer 17

Dopamine

Question 18

exposure to which factors can promote aggregation of a-synuclein?

Answer 18

iron
oxidants
nitration
exposure to environmental toxins

Question 19

Dopamine induced a-synuclein oligomers are not ______ T reactive

Answer 19

thioflavin T reactive (widely used to visualize and quantify the presence of misfolded protein aggregates called amyloid,)

Question 20

the presence of dopamine can change the aggregation properties of a-synuclein in they are..

Answer 20

resistant soluble oligomers (because the methoinine is oxidises)

Question 21

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?

Answer 21

A30P
A53T
E46K

Autosomal dominant inherited

Question 22

An ____ in a-synuclein gene dosage leads to increased levels of a-synuclein = more aggregation

Answer 22

increase

Question 23

transgenic mice expressing wild type a-synuclein have redced striatal ______ ______(involved in synthesis of dopamine) levels

Answer 23

transgenic mice expressing wild type a-synuclein have redced striatal tyrosine hydroxylase (involved in synthesis of dopamine) levels

Question 24

There are _ different secretory pathways to release a-synuclein

Answer 24

3

Question 25

Activation of ______ and ______ by a-synuclein are means to explain the inflammation associated with PD

Answer 25

activation of astrocytes and microglia by a-synuclein are means to explain the inflammation associated with PD

Question 26

The propagation of a-synuclein can also...

Answer 26

reduce lifespan (in injected m83 mice), particularly when injected at birth

Question 27

Which pathological aggregates are associated with a-synuclein, and what inheritance is it?

Answer 27

a-synuclein (dominant) - lewy bodies

Question 28

explain the Parkin gene's impact on PD | second most common one

Answer 28

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

Question 29

explain the PINK1 gene's impact on PD

Answer 29

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

Question 30

Explain the DJ-1 gene's impact on PD

Answer 30

DJ-1 (recessive) - no path found, onset 20-40 yrs Normally involved in oxidative stress response and mitochondrial function

Question 31

Explain the ATP13A2 gene's impact on PD

Answer 31

ATP13A2 (recessive), Lewy bodies, young onset

Question 32

Explain the LRRK2 gene's impact on PD | most common ______ inherited cause of familial PD

Answer 32

LRRK2 (Dominant - most common), usually Lewy bodies onset 30-50 yrs Mutations increase kinase activity LRRK2 also promotes mitochondrial and golgi fragmentation

Question 33

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?

Answer 33

ceramide glucoserebioside stabilises the a-synuclein oligomers

Question 34

parkin mutation inhibits ______, meaning more oligomers are preset

Answer 34

proteasomes

Question 35

LRRK2 can cause ____ fragmentation

Answer 35

Golgi fragmentation, results in increase formation of a-syn oligomers

Question 36

PINK1, DJ-1 and Parkin seem to prevent the fragmentation of ______ normally

Answer 36

mitochondria therefore loss of function of these result in less function mitochondria