Neuro diseases Flashcards
Define Neurodegeneration and Neurodegenerative disease
- Neurodegeneration = neuro (relating to neurons) + degeneration (progressive loss)
- Neurodegenerative disease = any disease caused by neurodegeneration
What do neuro diseases affect?
When do they begin?
• 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
Have a look at some examples
On table
Are Neurodegenerative diseases heterogenous and why?
• Neurodegenerative diseases are highly heterogeneous (varied in presentation), the reasons for this are:
o 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)
o Some diseases are inherently pleiotropic
Symptoms manifest differently in different people
(e.g. Parkinson’s disease symptoms unique to individual)
What are the patterns of these diseases?
- Molecular impairment somewhere in the cell
- Decreased transmission at synapse
- “Dying back” of neurites (axons and/or dendrites)
- Cell death
What is the distance between axon terminal and nucleus
a neuron’s “Achilles heel”
What are the common features of these diseases?
- Protein aggregation (“proteinopathies”)
- Lysosomal dysfunction
- Mitochondrial dysfunction
- Associated inflammation via activation of glia
What are the clinical and research problems?
• Neurodegenerative diseases rarely manifest overt signs and symptoms until long after neurodegeneration has begun
o Early treatment is impossible without early diagnosis
o Therapeutic challenge is considerable
• For CNS disorders, studies of affected tissue is very difficult until death
o 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.
Normal ageing = gradual decline in normal cognition, gradual changes in personality
What are the PATHOLOGICAL HALLMARKS of Alzheimers?
On images
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 causes alzheimers disease?
Aβ peptide is cleaved from a transmembrane protein called amyloid beta precursor protein (APP) by proteases
Mutations to three proteins involved in Aβ peptide processing are known to cause rare early onset forms of Alzheimer’s
• APP
• PSEN1 - Presenilin-1 and Presenilin-2; both a components of γ-secretase
• PSEN2 - Presenilin-1 and Presenilin-2; both a components of γ-secretase
What is tau and how does it cause alzheimers?
- Tau normally binds microtubules in axons
- Hyperphosphorylated tau is displaced causing:
Tangles
Destabilised microtubules
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 the 3 roles of microtubules in neurites?
- Structure/shape of cell
- Positioning of organelles
- Motorways for transporting
vesicular cargo
TAU OR AMYLOID?
• Still really controversial!
• Probably more evidence for amyloid, but…
o Therapies based on inhibiting Aβ aggregation so far haven’t worked
• Tangles and plaques may be red herrings
o Are they pathogenic or by-standers? Or even protective?
o Oligomeric forms of Aβ and tau are more likely to be pathogenic
• Could both be downstream of other factors?
What are the 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 motor and non-motor symptoms of parkinsons disease?
A movement disorder, with four ‘cardinal’ features
- Resting tremor
- Bradykinesia (slow movement)
- Rigidity
- Postural instability (fall over)
NON-MOTOR SYMPTOMS • >90% of patients display additional non-motor symptoms, including: o Depression & Anxiety o Loss of smell o Sleep disorders o Constipation o Dementia o Other psychiatric complications
What are the pathological hallmarks of PD?
On images
PATHOLOGICAL HALLMARKS 2
Proteinopathy again!
• Lewy bodies
o Intracellular protein aggregates
o Enriched in α-synuclein protein
• Normal role of α-synuclein is poorly understood (involved in neurotransmitter release)
• Lewy bodies not pathogenic, but ↑ α-synuclein is
Can PD be inherited?
• 10% of cases have a clear genetic cause
• Three rough categories
a. Early/Juvenile-onset recessive mitochondrial conditions
b. Late/later-onset (usually) autosomal dominant PD
c. Mutations that cause “PD-plus” conditions
What is early onset mitochondrial PD?
o Mitochondria have a finite lifespan due to oxidative stress
o Damaged mitochondria are selectively removed from the cell by “mitophagy” – autophagy of mitochondria
o 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
o Limitation: this PD is distinct from late-onset sporadic PD
(a whole different disease?)
What is late onset PD?
o 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 are GBA & α-SYNUCLEIN?
• GBA encodes GCase (β-glucocerebrosidase ),
a lysosomal enzyme
• α-synuclein is degraded in the lysosome
• They are connected…
How is PD and lysosomes related?
- 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
What have GWAS revealed?
- Risk genes
- Has shown many “cause genes” also influence risk
- Also found many new PD genes
- Now believed as much as 30% of PD risk is genetic
What are other 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?
• Neuroinflammation = activation of the immune system within the nervous system
• In the brain, this principally means activation of microglia
(astrocytes are also involved)
How can neuroinflammation lead to neurodegeneration?
On image
What are the protective and damaging roles of microglia?
• Reactive microglia can be protective of neurons or damaging
• Protective
o anti-inflammatory, e.g. TGFβ
o normal removal of unhealthy cells (i.e. homeostasis)
• Damaging
o pro-inflammatory, e.g. IL-1, TNF-α
o response to pathogens etc
(i.e. damage to neurons = ‘collateral damage’)
How is aging related to microglia?
Aging induces a shift towards production of damaging reactive microglia, due to changes in microglial gene expression - NEUROINFLAMMAGING
How is PD related to the gut and brain?
- Lewy body pathology in gut often precedes pathology in brain
- Evidence that gut inflammation is sufficient to cause gut Lewy bodies
- Spread to brain via vagus nerve?
- Role for microbiota?
What are the other effects of aging?
- Shortening of telomeres in adult stem cells
- Increased reactive oxygen species
- 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?!
