Neurodegenerative Diseases Flashcards
What are the basic characteristics of neurodegenerative diseases?
Affect the CNS or PNS (or both)
Begin at any stage of life
- The most common ones are associated with ageing
- Rarer types of neurodegenerative disease start in childhood or even from birth
- Earlier age of onset = greater genetic contribution
- Later age of onset = more likely a sporadic (or idiopathic) disease
Name 7 neurodegenerative diseases, their age of onset and whether they affect the PNS or CNS?
Alzheimer’s disease (AD)
~65 and over
CNS
Huntington’s disease (HD)
~40
CNS
Parkinson’s disease (PD)
60 to 65 (and over)
CNS
Motor Neurone disease
(Amyotrophic lateral sclerosis – ALS)
40-70
PNS
Multiple sclerosis (MS)
20-50
CNS
Spinocerebellar ataxia (SCA)
~30-40
CNS (some PNS)
Spinal muscular atrophy (SMA)
From birth
PNS
How are neurodegenerative diseases heterogeneous?
Neurodegenerative diseases are highly heterogeneous
- Some disease names are really umbrella terms
Conditions with overlapping phenotypes, but distinct causes (e.g. at least 25 types of SCA from mutations in different genes)
- Some diseases are inherently pleiotropic
Symptoms manifest differently in different people
(e.g. Parkinson’s disease symptoms unique to individual)
What are the common neuronal features of NDs?
Many follow a similar pattern:
- Molecular impairment somewhere in the cell
- Decreased transmission at synapse
- “Dying back” of neurites (axons and/or dendrites)
- Cell death
Distance between axon terminal and nucleus= a neuron’s “Achilles heel”
What are the common molecular features of NDs?
Frequently involve:
- Protein aggregation (“proteinopathies”) - Lysosomal dysfunction - Mitochondrial dysfunction - Associated inflammation via activation of glia
What are the clinical difficulties of NDs?
Neurodegenerative diseases rarely manifest overt signs and symptoms until long after neurodegeneration has begun
- Early treatment is impossible without early diagnosis
- Therapeutic challenge is considerable
For CNS disorders, studies of affected tissue is very difficult until death
- Advanced brain pathology is of little help to understanding the causes
Neurodegenerative diseases remain incurable
What is dementia?
A decline in memory and other cognitive functions that impair quality of life
Impairments in dementia are distinct from “normal” cognitive lapses, e.g. not recognising family members and strong changes in personality is not the same as losing keys or forgetting someone’s name
Normal ageing = gradual decline in normal cognition, gradual changes in personality
What are the pathological hallmarks of Alzheimers’s?
Brain shrinkage Proteinopathies Amyloid plaques - Extracellular protein aggregates - Enriched in Aβ peptides Neurofibrillary tangles - Also called paired helical filaments - Intracellular protein aggregates Enriched in Tau protein
What are Aβ and APP?
Aβ peptide is cleaved from a transmembrane protein called amyloid-beta precursor protein (APP) by proteases
First by beta-secretase, then by gamma-secretase and the product accumulates as amyloid plaque outside of the cell
What is the amyloid hypothesis?
Mutations to three proteins involved in Aβ peptide processing are known to cause rare early onset forms of Alzheimer’s
- APP
- PSEN1 (Presenilin-1)
- PSEN2 (Presenilin-2) both a components of y-secretase
Since early 1990’s “Amyloid hypothesis of AD”, which states that Aβ and/or amyloid plaques are the cause of AD
However therapies based on inhibiting Aβ aggregation so far haven’t worked
What is Tau?
Tau normally binds to microtubules in axons
Hyperphosphorylated tau is displaced causing:
- Tangles
- Destabilised microtubules when Tau detaches from them
Why are microtubules important in neurites?
In all post-mitotic cells, microtubules have 3 main roles:
1. Structure/shape of cell 2. Positioning of organelles 3. Motorways for transporting vesicular cargo
What is the Tau hypothesis?
In typical late onset AD (i.e. not genetic forms of AD), neurofibrillary tangles are:
- Seen before amyloid plaques
- Well correlated with cell death and progression
Suggests Tau is upstream Aβ = Tau hypothesis
What are other risk factors of AD?
Down syndrome (APP is on chromosome 21)
Gender (more common in women)
High BP, Cardiovascular disease, Diabetes
Low education
Head injury
Smoking and drinking
Only a small genetic risk contribution for late-onset AD (APOE gene status most significant)
What are the cardinal features of Parkinson’s disease?
A movement disorder, with four ‘cardinal’ features:
1. Resting tremor 2. Bradykinesia (slow movement) 3. Rigidity 4. Postural instability (fall over)
What are the non-motor symptoms of PD?
>90% of patients display additional non-motor symptoms, including: Common: - Depression & Anxiety - Loss of smell - Sleep disorders - Constipation Less common but more frequent than general population: - Dementia - Other psychiatric complications
What are the pathological hallmarks of PD?
Loss of dopaminergic neurons of the substantia nigra
Proteinopathy again!
Lewy bodies
- Intracellular protein aggregates
- Enriched in α-synuclein protein
Normal role of α-synuclein is poorly understood (involved in neurotransmitter release)
Lewy bodies not pathogenic, but ↑ α-synuclein, that causes them, is
What are the causes of PD?
Familial PD
~10% of cases have a clear genetic cause
Three rough categories
1. Early/Juvenile-onset recessive mitochondrial conditions
2. Late/later-onset (usually) autosomal dominant PD
3. Mutations that cause “PD-plus” conditions- conditions that are rare and come with additional complications
how is early-onset mitochondrial PD caused?
Mitochondria have a finite lifespan due to oxidative stress
Damaged mitochondria are selectively removed from the cell by “mitophagy” – autophagy of mitochondria
Loss-of-function mutations in two proteins central to activating mitophagy – PINK1 and Parkin – cause EO PD
- Mutations in at least 3 other genes linked to mitochondrial stress responses also linked to EO PD
Limitation: this PD is distinct from late-onset sporadic PD (a whole different disease?)
- Progression is different etc. so may be a whole different disease
What causes late-onset genetic PD?
Some genetic causes found from kindred studies (like EO PD), but more limited, including:
- SNCA (α-synuclein) gene amplification
· Confirms that α-synuclein is pathogenic
- LRRK2 gain-of-function
- VPS35 gain-of-function
- GBA loss-of-function
What do GBA and α-synuclein do and how are they connected?
GBA encodes GCase (β-glucocerebrosidase ), a lysosomal enzyme
α-synuclein is degraded in the lysosome
They are connected…
Ordinarily is the GCase enzyme is trafficked into the lysosome from the Golgi/ER and the lysosome is healthy and able to act as the final part of mitophagy where it can degrade a-synuclein
In a mutation causing less GCase activity or expression impairs the lysosome leading to a reduction in a-synuclein
So now it can accumulate
If you don’t have a GBA mutation the alpha-synuclein increase inhibits the translocation of GCase into the lysosome causing an impaired lysosome
This has been described as a pathogenic feed-forward loop
How do PD genes play roles in lysosomes?
Other PD genes play roles in processes involving lysosomes
Consistently, autophagy is dysregulated in PD brains.
Problems in autophagy will also lead to mitochondrial dysfunction (↓ mitophagy)
Endocytic pathways are a big focus in PD research
How is Tau linked to PD?
Linkage of MAPT to PD was a big surprise
Neurofibrillary tangles can be found in PD brains (even in same cells as Lewy bodies), but not to any great extent
However:
- More NFTs in brains of LRRK2 PD
- Microtubule disruption long implicated in PD
What are the non-genetic risk factors of PD?
Gender (more common in men) Red hair (~2x risk) Head injury Not smoking, not consuming caffeine Herbicides, pesticides, insecticides Exposure to metals (i.e. welder) General anaesthesia
What is neuroinflammation and how does it happen?
Neuroinflammation = activation of the immune system within the nervous system
In the brain, this principally means activation of microglia (astrocytes are also involved)
Reactive microglia:
- Is an ameboid shape
- Is more motile
- Produces cytokines
- Eventually phagocytic
How are neuroinflammation and neurodegeneration connected?
Lets start with a neurotoxic insult such as injury, toxin, gene mutation etc
The damaged neuron releases factors that will activate the microglia
The microglia becomes reactive and it secretes various neurotoxic factors such as IL-1B, TNF-a and prostaglandins that will trigger more cell damage and cell death
We end up with another positive feed forward cycle
How does ageing affect microglia?
Reactive microglia can be protective of neurons or damaging
Protective
- anti-inflammatory, e.g. TGFβ
- normal removal of unhealthy cells (i.e. homeostasis)
Damaging
- pro-inflammatory, e.g. IL-1, TNF-α
- response to pathogens etc (i.e. damage to neurons = ‘collateral damage’)
- Aging induces a shift towards production of damaging reactive microglia, due to changes in microglial gene expression- Neuroinflammaging
What are the other effects in gene expression that come with ageing?
Shortening of telomeres in adult stem cells so cannot replace dying neurons as well
Increased reactive oxygen species so increased stress in neurons
Other changes in gene expression
- Altered Wnt signalling is a big focus in AD and PD
- Wnts are neuroprotective and neuromodulatory
- Wnt/β-catenin is decreased in adult brain
- Deregulated Wnts in developmental and geriatric neuro conditions?!
