Lecture 23 - Parkinson's Disease Flashcards

Question

Describe the propagation of α-synuclein observed in mice studies What is the significance of this?

Answer 1

When α-synuclein is inoculated intracerebrally, there is rapid, progressive neurodegeneration observed This study was done in mice Mutant α-synuclein from symptomatic mouse injected into non-symptomatic mouse: • Reduced life span • Spreading of α-synuclein from area of injection to other regions → Indicated that α-synuclein spreads and propagates throughout the brain once present in PD This may be what is seen in the Braak staging

Answer 2

* Through secretory vesicles * Multi-vesicular bodies → released in exosomes * Recycling endosome: release contents out into extracellular space The neurons are not dying, but rather are viable One neurone can deposit α-synuclein into the extracellular space (monomeric or aggregated) and it can be taken up by other cells e.g. • Astrocytes take it up → inflammation • Taken up by other neighbouring neurons → propagation

Answer 3

2nd most common genetic cause of Parkinsonism

Answer 4

• Cytosolic protein • Role in clearance of protein: - cellular ubiquitination / protein degradation pathway • i.e. it acts as ubiquitin ligase ``` Role in PD • Loss of Parkin • Non-ubiquitinated substrates accumulating in neurons • Altered protein turn-over → SN degeneration ``` • Autosomal recessive, loss of function mutations

Answer 5

Normal function: • Phosphorylation of TRAP1 • TRAP1 is a mitochondrial chaperone protein Increased phosphorylation of TRAP1 under oxidative stress In PD: • Mutations leads to loss of kinase activity

Answer 6

SNCA: Autosomal dominant Parkin: Autosomal-recessive PINK1: Autosomal recessive LRRK2: Autosomal dominant DJ-1: Autosomal recessive

Answer 7

Precise function unknown • Role in intracellular signalling? (its kinase domain is of the MAPKKK class) • Promotion of mitochondrial & golgi fragmentation PD: • Mutation → Increased kinase activity • Increased mitochondrial and golgi fragmentation

Answer 8

Function: • Unknown • Involved in modulating the oxidative stress response and mitochondrial function • Oxidative stress → DJ-1 translocated to outer mitochondrial membrane In PD: • Unknown

Answer 9

Familial ←------------→ Sporadic Genetic variants ←--→ Environment The more dominant the genetic variant, the less role the environmental needs to play

Answer 10

α-synuclein interacts with and inhibits Complex I of ETC → fragmentation → neuronal death PINK1, DJ-1 and Parkin all interact with the mitochondria Mutation in the genes for these proteins can lead to mitochondria dysfunction → Energy loss from cell → Cell death

Answer 11

Stages of PD based on where the Lewy bodies are deposited 6 stages Location of Lewy bodies: Stage 1: in dorsal motor nucleus of vagal nerve → olfactory structures Stage 2: Lower raphe nuclei → stress and panic responses Stage 3: SN → clinical diagnosis Stage 4: temporal mesocortex → memory and emotions Stage 5: temporal neocortex → memory and language Stage 6: Neocortex → primary sensory areas Progressive deposition of Lewy bodies Location of deposition relates to the clinical features seen at that time

Answer 12

Signifies aggregation of α-synuclein into amyloid plaques

Answer 13

Can reverse the aggregation and make it soluble

Answer 14

Alters the aggregating properties For example: • Aggregates more quickly (shortened lag phase) • Reaches a high level of aggregation

Answer 15

Enzyme for synthesis of dopamine In transgenic mice that were over-experssing α-synuclein: • Reduced levels of this enzyme → Reduced dopamine

Answer 16

Recombinant : from bacteria, i.e. has never been in a brain before When the recombinant α-synuclein was injected into asymptomatic, non-transgenic mice it spread to other regions

Answer 17

Injected mice: die at around 280 days • If injected very early (at birth) there is even sooner onset of death Non-injected mice: around 470 days Injection of the brain lysate reduces the life span of the transgenic mice

Answer 18

10-50 years: i.e. juvenile PD

Answer 19

70-80 years Later than the familial causes

Answer 20

Glucoscerebroside stabilises α-synuclein oligomers Normally it is broken down into ceremide in lysosomes Mutations in the protein that break down glucoscerebroside lead to increased α-synuclein aggregation

Answer 21

* Parkin: decreased protein degradation * LRRK2: Golgi fragmentation * Glucoscerebroside: stabilisation of α-synuclein oligomers * LRRK2: Mitochondria fragmentation → energy loss from cells