synucleopathies

Question 1

what is synucleopathies

Answer 1

Synucleinopathies are a group of neurodegenerative disorders in which the protein alpha-synuclein accumulates abnormally to form inclusions in the cell bodies or axons of neurons or oligodendrocytes.

Question 2

what is the most common synucleopathy

Answer 2

Parkinson’s disease (PD)

Question 3

which primary brain area do synucleopaties affect

Answer 3

Neuron loss and gliosis mainly in substantia nigra

this is the Dopaminergic pathway to basal ganglia: Movement control

Question 4

How is the substantia nigra affected

Answer 4

there is a loss of melanin containing dopaminergic neurons. (melanin = pigment)
this leads to nigrostriatal dysfunction –> affects the basal ganglia

Question 5

why is the function of the basal ganglia important

Answer 5

The “basal ganglia” refers to a group of subcortical nuclei responsible primarily for motor control, as well as other roles such as motor learning, executive functions and behaviors, and emotions.

Question 6

which misbalance occurs in PD

Answer 6

dopamine decrease and acetylcholine increase

Question 7

how do you diagnose PD

Answer 7

with a SPECT tracer (detects dopamine transporters in the brain)
–> further visualise with PET scan

Question 8

State the progression of PD

Answer 8

1. starts in the brain stem/olfactory bulb

2. spreads out to cortical areas

Question 9

Define the PD pathology

Answer 9

caused by Lewy bodies (aggregates of a-synuclein oligomers)
loss of synapses
loss of neuronal function

Question 10

what is a-synuclein

Answer 10

small synaptic protein, which plays a role in synaptic vesicle function.

loss of function results in decrease neurotransmitter release (dopamine decrease)

Question 11

what are the toxic function and loss of function of a-syn oligomers

Answer 11

loss of function:

1. disruption axonal transport
2. mitochondrial dysfunction
3. synaptic dysfunction
4. inhibition ubiquitin/proteasome system (leads to even more oligomers)

toxic function

1. oligomers
2. ROS production

Question 12

define the aggregation cascade in PD

Answer 12

monomers - oligomers - fibrils - Lewy bodies

Question 13

what did electron microscopy find in PD patient

Answer 13

Lewy bodies are ubiquitin positive (cause of consequence?)

Question 14

what are the 4 central themes in PD

Answer 14

1. ROS
2. UPS (ubiquitin-proteasome-system)
3. mitochondria
4. a-synuclein aggregation

Question 15

what is the difference between PD and Parkinsonism

Answer 15

Parkinsonism doesn’t have Lewy bodies. ( a-synuclein doesn’t play a role)

Question 16

how are microglia activated in PD

Answer 16

neuroinflammation is triggered by neuromelanin. Neuromelanin is released once the neuron dies, which triggers inflammatory responses (microglia)

Microglia cells activate the production of toxic cytokines which stimulate the degeneration of dopaminergic neurones even further

Question 17

can PD lead to dementia (PDD)

Answer 17

yes, of the damage spreads out to cortisol area’s this can affect memory

Question 18

Explain dementia with Lewy bodies (DLB)

Answer 18

This is a case of isolated dementia. The a-synuclein inclusions affect the brain, but not the substantia nigra. This is only found sporadically, not genetic. (Parkinsonism)

Question 19

what is the distinction between Parkinsonism, PD, PDD and LBD

Answer 19

Parkinsonism: Lewy bodies
PD : a-synucleopathies, Lewy bodies restricted to the brainstem and limbic regions
PDD : a-synucleopathies, Lewy bodies extends to the neocortex
DLB: Lewy bodies extends to the neocortex

Question 20

what are different treatments for PD

Answer 20

L-dopa: It is a precursor of dopamine which can enter the BBB

Question 21

what is the Hydrophobic aggregation core

Answer 21

NAC domain

Question 22

which mutation can stimulate altered/accumulate a-synuclein function

Answer 22

SNCA mutation

Question 23

which mutations cause UPS dysfunction

Answer 23

UCHL, PARK2, DJ1

Question 24

what induces Parkinsonism

Answer 24

MPTP, it affects the mitochondria