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Molecule to Malady > Lecture 23 > Flashcards

Lecture 23 Flashcards

1
Q

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

A

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

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2
Q

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

A

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

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3
Q

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

A

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

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4
Q

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

A

Pars compacta

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5
Q

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

A

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

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6
Q

What is the role of the striatum

A

planning and modulation of movement pathways

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7
Q

Neuronal loss mainly occurs in whcih region of the SN?

A

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

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8
Q

The major form of parkinson’s disease is?

A

sporadic

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9
Q

what are some proposed mediators for sporadic PD?

A

toxins such as pesticides
metals
drugs MPTP

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10
Q

true or false

Inherited PD can be both autosomal dominant or recessive

A

true

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11
Q

Which genes of been identified as PD causing

A 
alpha-synuclein (SNCA)
Parkin (PRKN)
Leucine-rich repeat kinase
DJ-I
PINK I
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12
Q

True or False

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

A

true

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13
Q

What are Lewy bodies?

A

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

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14
Q

a-synuclein is…

A

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

linked to learning or development of synaptic plasticity

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15
Q

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

A

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

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16
Q

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

A

toxic species

17
Q

______ can inhibit aggregation of a-synuclein

A

Dopamine

18
Q

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

A

iron
oxidants
nitration
exposure to environmental toxins

19
Q

Dopamine induced a-synuclein oligomers are not ______ T reactive

A

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

20
Q

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

A

resistant soluble oligomers (because the methoinine is oxidises)

21
Q

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?

A

A30P
A53T
E46K

Autosomal dominant inherited

22
Q

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

A

increase

23
Q

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

A

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

24
Q

There are _ different secretory pathways to release a-synuclein

A

3

25
Q

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

A

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

26
Q

The propagation of a-synuclein can also…

A

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

27
Q

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

A

a-synuclein (dominant) - lewy bodies

28
Q

explain the Parkin gene’s impact on PD

second most common one

A

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
29
Q

explain the PINK1 gene’s impact on PD

A

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

30
Q

Explain the DJ-1 gene’s impact on PD

A

DJ-1 (recessive) - no path found, onset 20-40 yrs

Normally involved in oxidative stress response and mitochondrial function

31
Q

Explain the ATP13A2 gene’s impact on PD

A

ATP13A2 (recessive), Lewy bodies, young onset

32
Q

Explain the LRRK2 gene’s impact on PD

most common ______ inherited cause of familial PD

A

LRRK2 (Dominant - most common), usually Lewy bodies

onset 30-50 yrs

Mutations increase kinase activity

LRRK2 also promotes mitochondrial and golgi fragmentation

33
Q

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?

A

ceramide

glucoserebioside stabilises the a-synuclein oligomers

34
Q

parkin mutation inhibits ______, meaning more oligomers are preset

A

proteasomes

35
Q

LRRK2 can cause ____ fragmentation

A

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

36
Q

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

A

mitochondria

therefore loss of function of these result in less function mitochondria

Molecule to Malady (36 decks)

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