Neurodegenerative diseases Flashcards
What is neurodegeneration?
= progressive loss of neurons
- Can affect both CNS and PNS
- Begin at any stage of life, but most common with aging, but some with childhood and from birth
What are exmaples of early and late age onset of neurodegenerative diseases?
Earlier age of onset = greater genetic contribution
Later age of onset = more likely to be sporadic disease
How are neurodegenerative diseases highly heterogenous?
Some diseases are really umbrella terms
- Conditions with overlapping phenotypes but distinct causes
Some diseases are inheritably pleiotropic
- Symptoms manifest differently in different people
What is a neurons “achilles heel”?
= distance between axon terminal and nucleus
- Weak point as things have to be transported such a long way
What is the common cycle in a neurodegenerative disease?
- Molecular impairment somewhere in the cell
- Decreased transmission at synapse
- “dying back” of neurites
- Cell death
What are some common features of neurodegenerative diseases?
- Protein aggregation
- Lysosomal dysfunction
- Mitochondrial dysfunction
- Associated inflammation via activation of gilia
Why are neurodegenerative diseases hard to diagnose and cure?
Diseases rarely show signs and symptoms until long after the neurodegeneration has begun
- Early treatment is impossible
- Therapeutic challenge is considerable
For CNS disorders, studies of affected tissue is very difficult until death
Remain uncurable
What is Alzhiemer’s?
Most common neurodegenerative disease and common cause of dementia
Age of onset over 65, 10% start from age 30 onwards (early onset cases)
50% of people aged 85% have this
AD is not a normal part of ageing - it’s a disorder
What is dementia?
= decline in memory and other cognitive functions that impair quality of life
They are distinct from normal cognitive lapses like loosing keys and forgetting a name
- Alzheimer’s included not recognising family, sudden changes in personality, getting lost
*normal ageing = gradual decline in normal cognition and changes in personality*
What are the pathological hallmarks of alzheimers?
Brain shrinkage
- Shrinkage of cerebral cortex
- Enlarged ventricles
- Shrinkage of hippocampus - memory part
Proteinopathies
- Amyloid plaques
- Extracellular and enriched in AB peptides
- Neurofibrillary tangles
- Intracellular and enriched in Tau protein
What are the causes of Dementia/alzheimer’s?
Amyloid hypothesis
AB = peptide produced by the cleavage of transmembrane protein, APP by proteases
- Mutations to three proteins involved in AB peptide processing are known to cause rare early onset forms of Alzheimer’s
- APP
- PSEN1
- PSEN2
*Amyloid hypothesis of AD - plaques are the major cause of AD
What are the causes of Dementia/alzheimer’s?
Tau hypothesis
Tau normally binds to microtubules in axons
- If it becomes hyperphosphorylated causes tangles and destabilised microtubules
Microtubules give shape and structure, positioning of organelles in dendrites but they also are motorways for transporting vesicular cargo
*Tau hypothesis of late onset of AD of neurofibrillary tangles (before plaques)
Tau upstream of AB
What are the risk factors for alzheimers?
- Down syndrome
- Gender (more in women)
- Low education
- Head injury
- Smoking and drinking
What is parkinson’s disease?
Onset usually 60-65, 10% before 45
Incurable
A movement disorder with 4 cardinal features:
- Resting tremor
- Bradykinesia (slow movement)
- Rigidity
- Postural instability (fall over)
Non-motor symptoms
- Depression and anxiety
- Loss of smell
- Sleep disorders
- Constipation
- Dementia
What are the pathological hallmarks of parkinson’s disease?
Loss of dopaminergic neurons of the substantia nigra
- (other brain regions are still affected with the different symptoms)
Proteinopathy
- Lewy bodies - intracellular and enriched in a synuclein protein
- Increase in a-synuclein is pathogenic
What are the genetic causes of Parkinson’s?
Early onset recessive mitochondrial conditions
- Mitochondria have finite lifespan due to oxidative stress so they are removed by mitophagy before damage occurs
- Loss of function mutations 2 proteins central to activating mitophagy cause early onset PD
Late onset autosomal dominant PD
- SNCA gene amplification study confirms that a-synuclein is pathogenic
Mutations that cause PD-plus conditions - very rare
What is GCase?
A lysosomal enzyme which is encoded by GBA
- When you have less activity of GCase - lysosome becomes impaired itself - lead to reduction in autophagy and a-synuclein will accumulate –> are pathogenic
- **if you don’t have less activity of GCase but have high levels of a-synuclein
- A-synuclein will inhibit the translocation of Gcase into the lysosome –> impaired lysosome and leads to cell death
Problems in autophagy will lead to mitochondrial dysfunction –> decrease in mitophagy
What are the risk factors to Parkinsons?
- Red hair
- Head injury
- Not smoking, not consuming caffeine
- Exposure to metals
- Exposure to pesticides and herbicides
What is neuroinflammation?
= activation of immune system within the nervous system
- Activation of micro gilia in the brain
What can reactive microgila be?
Protective of neurons
- Anti-inflammatory
- Normal removal of unhealthy cells
Damaging of neurons
- Pro-inflammatory
- Response to pathogens
**ageing induces a shift towards production of damaging reactive microglia, due to changes in microglial gene expression
