Mitochondria in Parkinson's disease Flashcards Preview

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Flashcards in Mitochondria in Parkinson's disease Deck (41):

What are the symptoms of PD?

tremor-4-7Hz- lost upon purposeful movements
these are the main motor symptoms


What are many mutations involved in PD?

They are associate with some part of the ubiquitin proteasome system


What has been strongly suggested to cause PD?

mitochondrial dysfunction associated with oxidative stress ad PINK1 and DJ1 seem to be involved in this
- could also be due to changes in mitophagy leading to mitochondrial dysfunction and the production of ros
- dysfunctional kinases are another suggestion as they disrupt phosphorylation


What did an experiment do to look at the bioenergetics of PD?

in post mortems they compared mitochondrial enzyme activities in the brains of control patients and PD patients
- they dissected out the substantia nigra and determined the protein content


What did the experiment show about the bioenergetics of PD?

- measured total mitochondrial activity (citrate synthase) and this was the same in both groups
- measured complex 1 and 3 activity (NADH cytochrome C reductase) and there was a significant reduction in PD patients
- measured complex 2 and 3 activity (succinate cytochrome c reductase) and this was analagous in both groups
- normalised complex 1 activity and it demonstrated a decline


Why is it important neurones receive enough energy ?

neurones are the most metabolically active cells in the body so they require a lot of energy which is provided to them by the mitochondria
- needed to maintain ionic gradients for neurotransmitter release so action potentials can be generated


What do deficiencies in the electron transport chain cause ?

generate ROS which can cause damage to the cell membrane and organelles- causes activation of apoptotic and necrotic pathways


What was seen in the frontal cortex of PD patients?

exactly the same as in the subtantia nigra
- reductions only in complex 1 activity


What toxic substances can induce PD?

rotenone- also used as an insecticide


What is the story of barry kidston?

- made his own recreational amphetamines- MPPP
- took a short cut one time and produced MPPP contaminated with MPTP
- when he injected this it caused burning sensations and then over 3 days he had developed severe bradykinesia
- in A&E diagnosed him with catatonic schizophrenia and gave him haloperidol which made it worse- also received ECT and the had no effect
- then diagnosed him with PD and gave him L-DOPA and this improved his mobility


What happened when they looked at traces of what kidston had taken and what did they do with it ?

found that he had contaminated his MPPP with MPTP
so they injected mice with MPTP and they initially developed bradykinesia and rigidity but it wore off so they didn't think it was the MPTP that has given barry the PD


What happened to barry in the end?

he died of overdosing on heroine but he was also overdosing on his PD treatments
they then did post morterm analysis of his brain and it showed all the pathological signs of PD such as loss of the SN


What happened in San Jose/Watsonville USA?

6 young individiuals all developed rapid onset parkinsons
- they were all heroine addicts
- they all looked much older than they actually were
- they were given L-DOPA and it improved symptoms
- found out that the synthetic heroine was contaminated with MPPP and MPTP


What are the toxic symptoms of MPTP?

total immobility
increased tone
fixed stare, lack of blinking
constant drooling
cogwheel rigidity
pill rolling- classic tremor seen in PD


In 1983 what did they decide to do ?

they decided to inject MPTP into rhesus monkeys instead and this caused the development of a classic type of parkinson- behaviourally and anatomically - relieved by L-DOPA


What happens when MPTP is added to non-neuronal cells

MTPT added to non-neuronal cells on its own it is not toxic


What happened in vivo that causes MPTP to become toxic?

it gets converted to MPP+ which is toxic
-converted to MPP+ by MAO-B not A


What did inhibitors of MAO-A and MAO-B show?

MAO-A inhibitors had no effect whereas MAO-B inhibitors prevented toxicity so therefore oxidation of MPTP by MAO-B is fundamental


How does MPTP cause toxicity in dopaminergic neurones ?

even though dopaminergic neurones dont contain MAO-B, astrocytes do
- astrocytes uptake MPTP and convert it to MPP+ and then this is taken up into neurones by the plasmalemma DA transporter enabling it to accumulate and cause toxicity


What does mazindol do ?

it blocks DA transport and therefore prevents MPTP toxicity


Why are striatal neurones particularly sensitive to MPP+ ?

because they contain neuromelanin and the MPP+ binds to this allowing it to persist


How does MPP+ kill neurones?

it inhibits complex 1 of mitochondrial respiratory chain causing a rapid decrease in ATP synthesis leading to cell damage and death
- also causes oxidative stress and disruption of intracellular calcium homeostasis


What is another reason why MPTP is able to cause toxicity in the brain ?

because it can easily cross the BBB because it is not charged and there it can easily be converted to MPP+


What does inhibition of complex 1 cause?

- reduction in oxidative phosphorylation
- loss of calcium homeostasis
- increased ROS
- increased lipid peroxidation


What are the genetic models of PD?



What is alpha synucleins involvement in PD?

mutations in the gene were the first identified familial form
identical to sporadic forms, just earlier onset and faster progression


What were the differences between mice expressing low levels of mutant alpha syn compared to those expressing high levels ?

low expression= mitochondria look normal
high expression= lower levels of mitochondria and they appear to be undergoing autophagy


What does the A53T alpha-syn mutation cause?

it increases autophagy- too much mitochondrial turnover
- it can inhibit complex 1 causing changes in the mitochondria which precedes motor symptoms


What is LRRK2?

leucine-rich repeat kinase 2 gene
mutations cause 7% of familial late onset autosomal dominant parkinsonsim cases
causes lewy bodies and nigrostriatial neuronal loss


What are most mutations in LRRK2 and what did experiments show about it ?

most mutations cause increased kinase activity- gain of function mutations

experiments showed greater hoechst staining which is indicative of cell death in the mutant LRRK2 mice compared to WT and the cells demonstrating death colocallised with GFP labelling which was highlighting LRRK2


What do mutations in parkin cause?

50% of familial autosomal recessive early onset -pre 45yrs PD
Nigral neuronal loss but no lewy bodies

prevent recognition/ubiquitination


What does parkin do ?

it protects mitochondria from oxidative damage- may also have other functions
protects them from chemical toxins such as rotenone and MPTP


What was seen in Tg parkin KO mice ?

they had impaired oxidative phosphorylation in striatal mitochondria


What are the roles of parkin ?

important for regulating mitochondria by promoting mitophagy and by promoting mitochondrial elimination by ubiquitination


What is PINK-1?

mitochondrial serine/threonine kinase - another kinase
involved in early onset PD


What is the role of PINK1?

it is neuroprotective - protects against apoptotic cell death- mutants cant do this


What can PINK1 mutants not do ?

they can't
- restore mitchondrial membrane potential in PINK-1 KO SN neurones
- restore mitochondrial morphology in PINK1 KO SN neurones
-restore mitochondrial ROS handling in PINK1 KO SN neurones


What is PINK1 involved in ?

membrane potential
ability to handle ROS


What is DJ1?

it is an anti oxidative stress sensor- neuroprotective
it is a chaperones- preventing alpha-syn aggregation


What do mutations in DJ1 cause?

cause early onset autosomal recessive PD


What happens to DJ1 when cells are exposed to oxidants?

it relocates to the mitochondria