23. Neurodegenerative Disorders and Treatments Flashcards
What is oxidative stress?
Excess reactive species that overwhelm endogenous anti-oxidants
Leads to necrosis, apoptosis, senescence
What is parkinson’s disease caused by?
Loss of dopamine-producing brain cells
What are the four primary symptoms of parkinsons?
Tremor
Rigidity
Bradykinesia (slow movement)
Postural instability
What is the initial for parkinsons disease?
Levodopa (converted to dopamine) with Carbidopa (delays conversion until it reaches brain)
Anticholinergics (block acetylcholine)
What do treatments alleviate?
Bradykinesia and rigidity
What proteins are mutated, causing parkinsons disease?
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
What are some treatments other than Levodopa, carbidopa and anticholinergics?
Deep brain stimulation
- electrodes in subthalmic nucleus
Better than drug treatments
Stem cells therapies being considered
Gene transfer
What cell type is being considered in PD stem cell therapy?
ESC, tumour a problem
Autologous transplantation with iPS considered best
What is the best model for gene transfer therapy in PD?
Monkey model
Preferably aged
What is the mechanism being used for gene transfer in parkinsons disease?
AAV2-AADC/GAD (adeno associated virus2-aminoacid/ glutamic acid decarboxylase)
Enhances conversion of levodopa to dopamine
What is alzheimers disease?
Progressive brain disease that slowly destroys memory and thinking skills - Most common cause of dementia
What is alzheimers caused by?
massive denegeration of neurons
Increased astrocytes
Increased microglia attempting to phagocytose B-amyloid plaques
What are B-amyloid plaques and how do they form?
Amyloid precurser protein is cleaved by BACE, forming B-amyloid
Leads to neural tangles, tau
What gene is linked to late onset alzheimers?
APOE - apolipoprotein E gene
How can oxidative stress potentially cause alzheimers?
ROS increases b-amyloid (BA)
Disruptions to lysosomal degradation of protein aggregates
Is AB cause or consequence?
What are some current treatments for alzheimers?
Donepezil Rivastigmine Galantamine } mild to moderate Memantine - (moderate to severe) Regulating neurotransmitters
What are clinical trials investigating?
Resveratrol for oxidative stress
Neuroprotectants
Vaccination with AB42
Combinatorial approach, diet, excercise, vitamins etc
What cell based therapies are being investigated for alzheimers disease?
Human adipose derived stem cells improved behaviour
What is gene transfer based therapies are being investigated in the treatment of alzheimers?
Directly injected NGF gene into brain, via viral vector
What is Amyotrophic Lateral Sclerosis (ALS)?
Lou Gehrigs disease
Motor neurons gradually lost
Characterised by defects in Ca2 loading
Loss of glutamate transporters in astrocytes
What is the mutation associated with amyotrophic lateral sclerosis (ALS)?
Superoxide dismutase 1 is mutated (mtSOD1)
What does the superoxide dismutase 1 mutation cause?
Oxidate Stress:
Disruption Ca2 channels
Blocks anti-apoptotic actions of BLC-2
Myelin disruptions
What are some potential treatments for Amyotrophic lateral sclerosis?
Riluzole with lithium - anti-glutamate agents
Antioxidants in animal models: promising
Depramipexole: Neuroprotectant in trials
What is huntingtons disease?
Genetically programmed degeneration of brain cells due to mutant HTT, containing triplet CAG repeats
What are the symptoms of huntingtons disease?
Uncontrolled movements
Loss of intellectual faculties
Emotional disturbance
What sort of mutation (recessive or dominant) is that which causes huntingtons?
Autosomal dominant mutation leading to loss of neurons and astrocytes
