W3 Cell death and neurodegeneration in the CNS PDF

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Cell death and neurodegeneration in the CNS -

Neurons from birth have to survive until death We can cope with normal neuronal loss, but excessive loss can result in dementia Dementia affects >24 million people worldwide o Alzheimer’s account for >60% of all dementias o If you reach 80, you have a 20% chance of developing Alzheimer’s o Expected to reach 80 million people by 2040

What causes neurodegenerative disease? - Environment and lifestyle can impact dementia o Diet o Exercise o Smoking o Alcohol o Social activity o Mental activity o Heavy metal and toxins? Mutations in a wide range of genes are found in familial forms of neurodegenerative disease - Mutations in the amyloid precursor protein (APP) cause familial Alzheimer’s - Mutation in alpha-synuclein cause familial Parkinson’s disease - Mutations in SOD1 cause familial MND - Mutations in TDP-43 cause familial MND and prefrontal temporal dementia - Mutations in numerous other genes now implicated in each of these conditions Nucleotide repeats can also cause disease - A trinucleotide repeat in the Huntington gene causes Huntington’s Chorea - A hexanucleotide repeat in C9ORF72 is the most common cause of familial MND ~40% De Novo mutations can cause disease - Mutations do not need to be inherited - De novo mutations can arise in father’s sperm or mothers egg (80% in sperm) - 1 – 3% of sporadic NMD caused by new SOD1 mutations and 5% caused by new C9ORF72 expansion The same proteins can be implicated in the disease in the absence of mutations (only a few may have the mutation but all have aggregates) - amyloid plaques in all Alzheimer’s patients - Synuclein aggregates in all Parkinson’s disease patients - TDP-43 aggregates in essentially all MND patients

Huntington’s Chorea - A disease of mid-adult life - Onset 38 – 42 years’ old - Personality disturbance - Twist and turn in dance like motion - Death (mean 17 years post onset) -

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Autosomal dominant o Prevalence ~1 per 10,000 of population of Western European decent and 1 per 1,000,000 of Asian and African decent o ~30,000 people in USA have the disease o ~150,000 have a 50% risk gene localised to chromosome 4 Huntingtin gene which has a polyglutamine repeat sequence caused by a trinucleotide repeat expansion

When the gene has more than 36 copies, the DNA replication process becomes unstable and the number of repeats can change in successive generations. This can

mean that in a parent without HD but with a count close to 36, the count may increase above the threshold that causes HD Huntingtin - Mice lacking the gene do not get the disease - Expression of the mutant gene, or only the extended CAG repeat, can induce disease in mice and this classifies it as a “gain-of-toxic function” disease - Inclusion bodies containing mHtt aggregates build up selectively in vulnerable neurons – eventually in the nucleus - Aggregates can interact with transcription factors and modulate gene expression - Cell death follows – but mechanism not clear Motor neurone disease/ amyotrophic lateral sclerosis/ Lou Gehrig’s disease - Excessive loss of motor neurons in the spinal cord, brainstem and motor cortex - Age of onset typically 50 – 60 with life expectancy 5 years after onset - 10% of MND is familial (mutations identified in SOD1, TDP-43, FUS1) - A hexanucleotide repeat recently identified in C90RF72 - The same gene defects accounts for ~15% of the sporadic disease with C90RF72 being most common at ~5% of sporadic cases - SOD1 and RDP-43 can form toxic protein aggregates - The hexanucleotide repeat (up to 20kb) forms nuclear inclusions and can generate toxic peptides Progressive symptoms - A motor neuron will innervate many muscle fibers – this is the motor unit - If a motor neuron dies, others take over the territory by a process called compensatory sprouting and this increases the size of the motor unit - However, capacity to this is limited and motor units are eventually lost - The disease state is characterised by the excessive loss of motor units and severe muscular dystrophy - The important point is that in all disease states a considerable amount of damage is done before symptoms become apparent Non neuronal cells play a major role in propagating the disease - Microglia become activated and release toxic factors (NO, TNF alpha) that can drive neuroinflammation - Astrocytes become activated, release toxic factors, and lose their ability to recycle glutamate resulting in excitotoxicity How do protein aggregates form – prion hypothesis - Proteins can exist in folded and unfolded state - Unfolded state is rare and prone to aggregation - Disease mutation increases probability - Nucleation and propagation

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How does spreading occur? Thought to be transmission of protein aggregates from one cell to another

What actually kills neurons in neurodegenerative disease states? - Excitotoxicity

o arises when glutamate accumulates at synapses  excessive release  epilepsy  loss of Ca2+ homeostasis due to ATP rundown after stroke  defective uptake  loss of EAAT (eg in MND/ALS) can lead to increased synaptic levles  reversal of transporters  energy depletion after stroke o results in accumulation of Ca2+ at the synapse  Ca2+ can damage mitochondria and in addition can activate proteases, endonucleases, stress activated kinases, phospholipases and nitric oxide synthase  Can result from  Head trauma  Cerebral ischaemia (stroke)  Alzheimer’s, Parkinson’s and Huntington’s  Motor neurone disease (ALS)  Damage following intense seizure activity (epilepsy) and alcohol withdrawal  Age related cognitive decline How might we mitigate against the disease and/or limit damage? - Replacement therapy o L-dopa for Parkinson’s disease (long term L-Dopa use can be toxic leading to dyskinesia) o Cholinesterase inhibitors for Alzheimer’s - Excitotoxicity o Glutamate receptor antagonists (AMPA, NMDA)

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o Na channel antagonists (too toxic) o Voltage gated calcium channel antagonists (too toxic) o Use partial antagonists Anti-inflammatory drugs o COX 1 or 2 inhibitors Target the cause of the disease – limit the accumulation of toxic proteins o Beta and gamme secretase inhibitors to prevent generation of toxic Abeta peptides o Immunisation strategies to remove toxic Abeta peptides and other toxic aggregates (eg Tau and synuclein)

Amyloid plaque reduction in the human brain with monoclonal antibodies to oligomers and plaques - Is removing it sufficient or has the damage already been done...