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
