23. Neurodegenerative Disorders and Treatments

Question 1

What is oxidative stress?

Answer 1

Excess reactive species that overwhelm endogenous anti-oxidants
Leads to necrosis, apoptosis, senescence

Question 2

What is parkinson’s disease caused by?

Answer 2

Loss of dopamine-producing brain cells

Question 3

What are the four primary symptoms of parkinsons?

Answer 3

Tremor
Rigidity
Bradykinesia (slow movement)
Postural instability

Question 4

What is the initial for parkinsons disease?

Answer 4

Levodopa (converted to dopamine)
with
Carbidopa (delays conversion until it reaches brain)

Anticholinergics (block acetylcholine)

Question 5

What do treatments alleviate?

Answer 5

Bradykinesia and rigidity

Question 6

What proteins are mutated, causing parkinsons disease?

Answer 6

Leucine-rich repeat kinase 2 (LRRK2)
Synucelin
Parkin
DJ1 and PTEN-induced putative kinase 1

Mitochondrial outermembrane
- Involved in reactive oxygen species protection

Increase in astrocyte reactivity
Micoglia amplify initial damage

Question 7

What are some treatments other than Levodopa, carbidopa and anticholinergics?

Answer 7

Deep brain stimulation
- electrodes in subthalmic nucleus
Better than drug treatments

Stem cells therapies being considered

Gene transfer

Question 8

What cell type is being considered in PD stem cell therapy?

Answer 8

ESC, tumour a problem

Autologous transplantation with iPS considered best

Question 9

What is the best model for gene transfer therapy in PD?

Answer 9

Monkey model

Preferably aged

Question 10

What is the mechanism being used for gene transfer in parkinsons disease?

Answer 10

AAV2-AADC/GAD (adeno associated virus2-aminoacid/ glutamic acid decarboxylase)

Enhances conversion of levodopa to dopamine

Question 11

What is alzheimers disease?

Answer 11

Progressive brain disease that slowly destroys memory and thinking skills - Most common cause of dementia

Question 12

What is alzheimers caused by?

Answer 12

massive denegeration of neurons

Increased astrocytes

Increased microglia attempting to phagocytose B-amyloid plaques

Question 13

What are B-amyloid plaques and how do they form?

Answer 13

Amyloid precurser protein is cleaved by BACE, forming B-amyloid

Leads to neural tangles, tau

Question 14

What gene is linked to late onset alzheimers?

Answer 14

APOE - apolipoprotein E gene

Question 15

How can oxidative stress potentially cause alzheimers?

Answer 15

ROS increases b-amyloid (BA)
Disruptions to lysosomal degradation of protein aggregates

Is AB cause or consequence?

Question 16

What are some current treatments for alzheimers?

Answer 16

Donepezil
Rivastigmine
Galantamine } mild to moderate
Memantine - (moderate to severe)
Regulating neurotransmitters

Question 17

What are clinical trials investigating?

Answer 17

Resveratrol for oxidative stress
Neuroprotectants
Vaccination with AB42
Combinatorial approach, diet, excercise, vitamins etc

Question 18

What cell based therapies are being investigated for alzheimers disease?

Answer 18

Human adipose derived stem cells improved behaviour

Question 19

What is gene transfer based therapies are being investigated in the treatment of alzheimers?

Answer 19

Directly injected NGF gene into brain, via viral vector

Question 20

What is Amyotrophic Lateral Sclerosis (ALS)?

Answer 20

Lou Gehrigs disease
Motor neurons gradually lost
Characterised by defects in Ca2 loading
Loss of glutamate transporters in astrocytes

Question 21

What is the mutation associated with amyotrophic lateral sclerosis (ALS)?

Answer 21

Superoxide dismutase 1 is mutated (mtSOD1)

Question 22

What does the superoxide dismutase 1 mutation cause?

Answer 22

Oxidate Stress:
Disruption Ca2 channels
Blocks anti-apoptotic actions of BLC-2
Myelin disruptions

Question 23

What are some potential treatments for Amyotrophic lateral sclerosis?

Answer 23

Riluzole with lithium - anti-glutamate agents

Antioxidants in animal models: promising

Depramipexole: Neuroprotectant in trials

Question 24

What is huntingtons disease?

Answer 24

Genetically programmed degeneration of brain cells due to mutant HTT, containing triplet CAG repeats

Question 25

What are the symptoms of huntingtons disease?

Answer 25

Uncontrolled movements
Loss of intellectual faculties
Emotional disturbance

Question 26

What sort of mutation (recessive or dominant) is that which causes huntingtons?

Answer 26

Autosomal dominant mutation leading to loss of neurons and astrocytes