Neurodegenerative Diseases Flashcards
What does Neurodegeneration mean ?
The progressive loss of neurons
What are neurodegenerative diseases ?
This is any disease which can cause a loss of neurons
What are the difference in causes based on the age of onset ?
Childhood-Rare
Earlier age of onset -Genetic contribution
Later age of onset -More likely a sporadic/idiopathic (Unkown cause )cause
What are some examples of Neurodegenerative diseases?
Alzheimers -CNS Huntingtons -CNS Parkinsons -CNS Motor Neurone disease (ALS) -PNS Multiple sclerosis -CNS Spinocerebellar ataxia -CNS (some PNS) Spinal muscular atrophy -CN
Why are neurodegenerative diseases highly heterogeneous ?
This is because many of the disease names are usually umbrella terms
- Conditions with overlapping phenotypes but distinct causes
for e.g -
SCA has 25 types of mutations in different gene s
2.Some diseases are inherently pleiotropic:
Symptoms will manifest in different ways in different people
What pattern do neurodegenerative diseases follow ?
1.Molecular impairement somewhere within the cell
- Decreased transmission at synapse
- Most likely at axon terminal - Dying back at neurites -At the synapse (Axons and or dendrites
- Cell death
The distance between the nucleus and the synaptic terminals is a weak point because things need to be transported a long way.
“Achilles heel “
What are some common features of neurodegenerative diseases ?
- Protein aggregation (Porteinopathies )
- Lysosomal dysfunction
- Mitochondrial dysfunction
- Assosciated inflammation via activation of glia
What are the clinical challenges and research difficulties of neurodegenerative diseases ?
They rarely manifest overt (open) signs and symptoms until long after neurodegeneration has begun.
Early treatment is therefore impossible without early diagnosis
For CNS disorders studies of affected tissue is very difficult until death
They are all incurable
What is the most common neurodegenerative disease /dementia ?
Alzeihmers Disease
Onset is usually >65 years of age
What is dementia ?
This is the decline in memory and other cognitive functions that impair quality of life
What are pathological hallmarks ?
These are clear signs which indicate disease
Describe the pathological hallmarks of Alzheimer’s disease
1.Brain shrinkage
Shrinkage of hippocampus
Enlargement of ventricles
Cortex shrinks
2.Proteiopathies
Amyloid plaques
- Extracellular protein aggregates
- Enriched in A beta peptides
Neurofibrillary tangles
Also called paired helical filaments
Intracellular protein aggregates
Enriched in Tau protein
What is A beta and how does it form Amyloid plaques ?
A beta peptide is cleaved from a transmembrane protein called amyloid beta precursor protein (APP) by proteases.
Cleavage by Beta -Secretase and second enzyme called gamma-secretase and this release the A beta fragment which accumulates forming the Amyloid plaques.
What can cause rare early onset forms of Alzheimer’s?
Mutations in proteins involved in A beta peptide processing :
APP
PSEN1
PSEN2
These are both components of gamma-secretase
What is Tau and what can this protein cause ?
Tau is an intercellular proteinnormally binds microtubules in axons
Hyperphosphorylated by kinases.serine,tyrosine which displaces Tau:
Causes:
Tangles
Destabilisised Microtubules
What is the importance of microtubules in neurites ?
Neurites are projections from the cell body of a neuron
In post mitotic cells microtubules have three roles:
Structure/Shape of cell
Positioning of organelles
Motorways for transporting vesicular cargo
The distance between axon terminal and nucleus=Weak point
Outline the Tau hypothesis
In late onset AD, neurofibrillary tangles are:
seen before amyloid plaques
Well correlated with cell death and progression.
This therefore suggests that Tau is upstream A beta
What are some other risk factors of Alzeihmers
Down syndrome (APP is on chromosome 21)
Gender
High Bp ,Cardiovascular disease, Diabetes
Low education
Head injury
Smoking /drinking
Genetic (APOE gene status)
What are the symptoms of Parkinson’s ?
Movement disorder with four cardinal features
- Resting tremor
- Bradykinesia(slow movement)
- Rigidity
- Postural instability (falling over )
What are the non-motor symptoms?
Depression and Anxiety Loss of smell Sleep disorders Constipation Dementia Psychiatric complications
Outline the pathological hallmarks of Parkinson’s disease
1.Loss of dopaminergic neurons of the substantia
(neurons that produce the neurotransmitter dopamine)
Substantia nigra =Part of the basal ganglia in the mid brain.
2.Proteinopathy
Lewy bodies
Intracellular protein aggregates
Enriched in alpha-synuclein proteins
Normal role of alpha-synuclein is poorly understood -involved in neurotransmitter release
Lewy bodies are not pathogenic but an increase in alpha-synuclein is.
What categories of PD can have genetic causes ?
- Early/juvenile onset recessive mitochondrial conditions
- Late/later onset autosomal dominant PD
- Mutations that cause PD plus conditions
Outline the early onset mitochondrial PD
Mitochondira have a finite life span due to oxidative stress
Damaged mitochondria are removed by mitophagy.
Loss of function mutations in two proteins central to activating mitophagy (PINK1/Parkin) cause EO PD )
Mutations in at least 3 other genes linked to mitochondrial stress responses also linked to EO PD.
Outline the late onset genetic PD
Some genetic causes found from kindred studies like EO PD but more limited :
Including
SNCA (a-synuclein) gene amplification
-confirms that a-synuclein is pathogenic
LRRK2 gain of function
VPS35 gain of function
GBA loss of function
How has GBA been linked to a-synuclein?
GBA encodes GCase (beta-glucoerebroisidase ) a lysosomal enzyme
a -synuclein is degraded in the lysosome via autophages processes
Describe what happens to the GCase enzyme in a healthy person
The GCase enzyme is trafficked into the lysosome from other organelles (The Golgi and ER).In the lysosome it is able to act as the final stage of autophophy where it can degrade a-synuclein meaning there isn’t accumulation and lewy bodies and parkinsons
Describe what happens if an individual inherits a GCase mutation GBA gene mutation?
They will have less activity /expression of GCase. This impairs the lysosome as there is less active GCase meaning it will not serve the last step of autophagy leading to accumulation of a-synucleins.
What happens if there is no GBA mutation but there is an increase in a-synucleins ?
The excess a-synucleins will inhibit the translocation of GCase into the lysosome thus also impairing the lysosome function.It will cause an increase in even more a-synucleins.Pathogenic feedforward loop.
There will be cell death
In what way can PD affect lysosomes?
Consistently leads to autophogy disregulated.
Problems in autophagy will also lead to mitochondrial dysfunction-Mitophogy
What gene found to be linked to Parkinsons disease was unexpected
MAPT which codes for Tau as Tau is found in Alzheimer’s.
Neurofibrillary tangles can be found in PD brains same cells as Lewy bodies.
More NFTS in brains of LRRK2 PD
Microtubules disruption long implicated in PD.
What are some risk factors ?
Gender Red hair Head injury Not smoking /not consuming caffeine Herbicides,pesticides,insecticides Exposure to metal General anaesthesia
What is Neuroinflammation ?
This is the activation of the immune system within the nervous system.
In the brain this means activation of microglia (astrocytes are also involved )
What are reactive microglia and what changes happen ?
It becomes a Ameboid shape (irregular shape )
More motile
Production of cytokines
Phagocytic (able to engulf cellular debris )
How is neuroinflammation involved in neurodegenratyion ?
Following neurotoxic insult there is a dying/damaged neuron and this will release factors (a-synuclein and other proetins )
This will activate the microglia which will release neurotoxic factors such as (IL-1B, TNF-a, prostaglandins) and this will trigger more cell damage /cell death.
This will create a forward loop.
What are the two types of active microglia?
Protective:
Anti-inflammatory e.g. TGFBeta
-Normal removal; of unhealthy cells -homeostasis
Damaging :
pro-inflammatory e.g. IL-1, TNF-alpha
-Response to pathogens etc
(ie damage to neurons =collateral damage )
How does ageing affect the type of active microglia we have ?
Ageing tends to induce a shift towards a production of damaging microglia due to changes in microglia gene expression
Neuroinflammaging
What are some other ways in which neuroinflammation triggers neurodegeneration
External trigger
Environmentla toxins
Pathogens
A-beta
What are some evidence for neuroinflammation being the cause ?
Many Alzheimer’s risk factors cause raised levels of circulating inflammatory cytokines.
High Bp-Cardiovascular disease, Diabetes , Smoking
Effects can cross the blood brain barrier
What is the PD gut-to-brain theory ?
Lewy body pathology in gut can often preced pathology in brain
evidence that gut inflammation is sufficient to cause gut Lewy bodies
May spread to brain via the vagus nerve
May be due to microbiota
(Increased constipation)
What other ways can ageing affect neurodegeneration?
Shortening of telomeres in adult stem cells
Increased reactive oxygen species
Gene expression
-Altered Wnt signalling is a big focus in AD and PD
Wnts are neuroprotective and neuromodulatory
Wnt/beta-catenin is decreased in the adult brain
Deregulated Wnt in developmental and geriatric neurological conditions
