HNS53, HNS54 Molecular Basis Of Neurological Diseases I and II Flashcards
Neurological diseases
- ***Huntington’s disease
- Infection (HIV, meningitis, prion etc.)
- Injury
- Autoimmune (Myasthenia gravis)
- Inflammation (Multiple sclerosis)
- ***Motor neuron disorders (Parkinson’s disease)
- Synaptic transmission
- ***Neurodegenerative (Alzheimer’s disease)
Huntington’s disease
Autosomal dominant
- every generation
- both male and female affected
- highly penetrant
Typically begin in mid-life (30-45)
NO current treatment to prevent / delay progression of HD
Clinical features of HD
- Motor
- Chorea
- Gait abnormalities
- In-coordination
- Dysarthria
- Eye movement abnormalities
- Rigidity / Bradykinesia / Dystonia (esp. in young onset cases) - Cognitive
- Subcortical structures
- Frontal type problems (impaired executive functions): problem solving, planning etc.
- Mental slowing
- Poor attention / memory difficulties
- Language generally well-preserved
- ALL patients will develop global dementia with time
- Need to check not depressed esp. they can get worse quickly - Psychiatric
- Personality change
- Apathy, irritability, disinhibition, emotionally labile
- Mood swings
- Social withdrawal
- Poor self care and alcoholism
- Criminal record due to mental problem - Other features (fits in young onset cases, sleep disturbance, weight loss)
Clinical stages of HD
- Early
- progressive emotional, psychiatric, cognitive disturbances - Later
- motor signs
- progressive dementia - Advanced
- unable to walk
- poor dietary intake
- long term institutional care - Swallowing difficulties —> Aspiration pneumonia
Neuropathology of HD
- Brain specific
- ***Striatal atrophy
- Prominent neuronal loss (Caudate nucleus + Putamen)
- Selective for **medium spiny neurons (Special type of **GABAergic inhibitory neurons)
Etiology of HD: Mapping HD gene
- Use genetic linkage
- Abnormal gene contain multiple **CAG repeats —> multiple **glutamine (abnormal Huntington (htt) protein)
- > 36 CAG repeats —> HD (>39 definitely pathogenic)
- larger number of repeats —> develop symptoms at earlier age
Huntington gene:
- > 200,000 base pairs, 67 exons
- 348kDa protein (3144 a.a.)
- Polyglutamine sequence (CAG repeats)
- ***Ubiquitous expression (highest levels in CNS neurons)
- ***Widespread subcellular localisation (clathrin-coated vesicles, endosomal compartment, microtubule)
Key cellular pathogenic mechanisms in HD
Multiple glutamine repeats (每一個獨立mechanism)
- Conformational change of protein —> unfolding / ***abnormal folding
- ***Accumulation in cytoplasm
- Impairment of calcium signaling in ER + homeostasis
- ***Mitochondrial dysfunction
- Translocate to nucleus (***impair BDNF gene transcription, form intranuclear inclusions)
- Alters ***vesicular transport and recycling
—> ALL eventually lead to Prominent loss of medium spiny neurons (Special type of ***GABAergic inhibitory neurons)
—> Striatal atrophy
Gene therapy of HD
AMT-130:
- consist of AAV5 vector
- carrying an **artificial micro-RNA —> tailored to **silence mutant Huntington gene
Parkinson’s disease
- 2nd most common neurodegenerative disorder
- ***Majority sporadic, 10-20% family history
- Monogenic rare
- ***Male > Female
- Autosomal Dominant / Recessive (both occur)
Clinical features of PD
四寶: Resting tremor, Muscle rigidity, Bradykinesia, Abnormal gait/posture
- Tremor-at-rest
- Bradykinesia, Hypokinesia, Akinesia
- Rigidity
- Flexed posture of neck, trunk, limbs
- Loss of postural reflexes
- Freezing phenomenon
***Pathological features
- Loss of monoamine neurons in Substantia nigra pars compacta + Locus ceruleus
- Presence of Lewy bodies (inclusion bodies within neuron containing α-Synuclein etc.) + ↑ Glial cells - Depigmentation
- loss of ***Neuromelanin (derived from oxidised dopamine) in Substantia nigra pars compacta + Locus ceruleus
Overall:
Dopamine depletion in Substantia nigra + Nigrostriatal pathway to Caudate + Putamen
—> ↑ inhibition of Thalamus + ↓ excitatory input to Motor cortex
—> Bradykinesia and other parkinsonism signs
Lewy bodies
- Intracellular eosinophilic masses made up of ***α-Synuclein and other proteins
- ***Pathologic hallmark of PD
- Not specific to PD, also found in other neurodegenerative diseases and normal elderly people
***Gene localisations identified for PD
- PARK1 gene —> Autosomal ***dominant inheritance —> α-Synuclein mutations and aggregation into Fibrillar forms —> Lewy bodies
- PARK2 gene —> Autosomal ***recessive inheritance —> inactivation of Ubiquitin ligase (Parkin) —> accumulation of Parkin substrates (targeted protein) in neurons —> Selective toxicity to Dopamine neurons
Dynamic aggregation processes of α-Synuclein
- α-Synuclein is unfolded in solution but form helix-like structures in association with membrane
- normally exist in equilibrium between membrane and cytosol
- Pathological conditions (Autosomal Dominant mutation of α-Synuclein gene):
α-Synuclein **aggregates via small oligomeric intermediates
—> larger **fibrillar forms (β-sheet)
—(+ Ubiquitin)—> ***Lewy bodies
Parkin protein
- E3 Ubiquitin ligase
- 2 domains: RING-box domain + Ubiquitin domain
- 465 a.a.
- Autosomal Recessive juvenile PD + Early onset Recessive PD
- Ubiquitin-Proteasome pathway:
- E1 transfer Ub to E2
—> E2-Ub attach to RING-box
—> transfer Ub to targeted protein
—> attachment of Polyubiquitin chains to targeted proteins (將Ubiquitin (死亡signal) attach落targeted protein度)
—> degradation
- ***Inactivation of E3 Ubiquitin ligase (Parkin) —> accumulation of Parkin substrates (targeted protein) in neurons —> Selective toxicity to Dopamine neurons - Protective role in mitochondria
- Dopaminergic neurons may also be more vulnerable because of ***intrinsic exposure to oxidative stress —> protein damage and misfolding
PD summary
- Neurodegenerative disease with movement disorder + neuropsychiatric clinical features
- Majority sporadic, some genetic forms
- Progressive, chronic, incurable
- ***Pathology:
1. Neuronal loss in Substantia nigra pars compacta + Locus coeruleus
2. Depigmentation (loss of Neuromelanin)
Example of gene mutation:
- **α-Synuclein accumulation —> **Lewy body
- ***Inactivation of Parkin —> E3 Ubiquitin ligase —> Proteins targeted for degradation
Alzheimer’s disease
- ***Age-dependent neurodegenerative disorder that results in progressive loss of cognitive function
- Memory loss, unusual behaviour, personality changes, decline in thinking abilities
- Burden of AD: emotional, physical, financial stress on family members
- most common cause of dementia among elderly in HK
Risk factors:
- Age
- Family history dementia esp. early onset
- Down’s syndrome
- Severe head injury
- Genetic factors
- Lifestyles
- Vascular risk factors?
Classification of AD
- By age of onset
- Early onset: <= 65
- Late onset: >65 - By family history
- ***Sporadic case ~90%
- Familial case ~10%
Cognitive features of AD
- ***Memory
- impaired anterograde episodic memory
- delayed recall of stories
- Word List learning
- impaired association (visual memory and new learning)
- working memory spared - Attentional + ***Executive deficits
- poor concentration
- problem with complex tasks
- selective attention
- executive functions
- Wisconsin Card Sorting test —> test working memory - ***Language and knowledge
- impaired semantic memory
- category fluency
- word definitions
- word finding esp. proper names
- later phonological and syntactic deficits - ***Visuospatial and Perceptual inabilities
- impaired drawing esp. 3D
- apraxia mainly conceptual
Neuropsychiatric features of AD
- Apathy
- Depression
- Anxiety
- Delusion (rare in early stage)
- Paranoia
- Phantom lodger (inability to recognize one’s own reflected image)
- Agitation and disruptive behaviour common later
Diagnostic criteria of AD
According to NINCDS-ADRDA alzheimer’s criteria:
“Probable AD”:
1. Deficits in >=2 areas of cognition
2. MMSE score <24, plus neuropsychological test evaluation
3. Progressive worsening of cognitive function
Diagnostic methods:
- ***Neuropsychological
- Structural imaging
- Functional ***imaging (PET, SPECT)
- ***Biological markers (CSF amyloid, tau protein etc.)
***Pathology of AD
- Shrinkage of Cortex (esp. Superior frontal association cortex)
- Shrinkage of Hippocampus (+ Entorhinal cortex, Inferior temporal cortex)
—> enlarged Ventricles
***Pathological hallmarks in AD brain
-
**Amyloid plaques
- Extracellular aggregation of **Amyloid-β protein, other association proteins, non-nerve cells -
**Neurofibrillary tangles
- Intracellular abnormal form of **microtubule associated protein: Tau —> Hyperphosphorylated —> captured in NFT —> microtubules destabilised + dissociation —> reduced axonal transport —> AD - Significant decrease in ACh transferase + Loss of cholinergic neurons
Familial AD
- ***Autosomal dominant families in Early onset AD
- ***Familial aggregation in Late onset cases (also Autosomal dominant, with age-dependence but high penetrance)
- ***MZ twins (~40-50%) vs DZ twins (~10-20%) concordance rate
***Genetics of Early onset AD
Three ***autosomal dominant genes responsible for almost ALL large early-onset AD families
- ***APP
- ***PSEN1 (most mutations and most families)
- ***PSEN2
Still, ~50% of early-onset AD cases remain genetically unexplained
APP processing and Amyloid plaque
One domain of ***Transmembrane protein
- β-secretase —> cleave APP to form C99 —> ***γ-secretase (encoded by PSEN1) —> Aβ40/Aβ42 (—> degraded by Neprilysin, IDE, APOE)
- α-secretase —> cleave APP to produce C83
Mutation of APP / PSEN1:
- affect cleavage activity —> ↑ Aβ40/Aβ42 —> Amyloid-β accumulation —> Amyloid plaque
Neurofibrillary tangles
Tau protein:
- structural protein in neuron
—> binds and **stabilise microtubule
—> help to **transport
Alzheimer’s disease: - Tau protein ***hyperphosphorylated —> Tau ***sequestered / captured in Neurofibrillary tangles —> loss of Tau binding to microtubules —> microtubule ***dissociation —> reduced ***axonal transport —> AD
ApoE: Risk factor of AD
Risk factor for ***Sporadic AD
Mechanism for association with AD: likely **Aβ clearance + **neuronal repair
Apolipoprotein E - transport plasma lipids within tissues - ***clearance of Amyloid-β at BBB - immune response - synaptic maintenance - 3 alleles: —> ε3 (most common, normal allele) —> ε2 (protective: ↓ frequency in AD cases but risk factor for CVD) —> ε4 (risk allele: ↑ frequency in AD cases)
- **ε4 allele:
- ↑ risk of developing AD
- ↓ age of onset of AD
Potential treatment for AD
Aducanumab
- targets aggregated forms of β-amyloid —> reducing its buildup
- antibody given IV once a month
Amyotrophic lateral sclerosis (ALS)
- ***Sporadic ALS: 90%
- Familial ALS: 10%
- average age of ALS onset: 55
- 50% patients die after 3 years
Symptoms of ALS
- Tripping, stumbling, falling
- Loss of muscle control and strength in hands, arms
- Difficulty speaking, swallowing, breathing
- Chronic fatigue, muscle twitching / cramping
Caused by:
- Upper motor neuron damage:
- Stiffness (spasticity)
- Muscle twitching (fasciculations)
- Muscle shaking (clonus) - Lower motor neuron damage:
- Muscle weakness
- Muscle shrinking (atrophy)
Spinal onset vs Bulbar onset of ALS
Spinal onset (problem begin in limbs):
- 75%
- 6 months of progressive weakness of hand grip
- fasciculations of muscle in affected limb
- cramps and spasms
- weight loss +
Bulbar onset (problem begin with speaking / swallowing):
- 25%
- commoner in elderly women
- 9 months of progressive difficulty in speaking / swallowing
- weight loss +++
- inappropriate laughing and crying
- breathless when lying flat
Diagnosis of ALS
- ***NO diagnostic test
- Mainly based on progressive pure motor syndrome
- not explained by lesion in a single anatomical site
—> mean delay in diagnosis: 1 year
- EMG: supportive paraclinical test
- inappropriate laughing / crying
Pathology of ALS
- ***Brain atrophy (some areas more severe)
- Neuronal loss in ***Corticospinal tract
- Unique microscopic features
- **Bunina bodies in motor neurons
- **“Skeins”, **Hyaline bodies, **Dystrophic neurites in anterior horn cells
Genetics of ALS
- ***SOD1 gene
- Autosomal dominant
- typical ALS - ***Dynactin gene
- Autosomal dominant
- adult onset, slow progressive, early vocal cord paralysis
SOD1 mutations
- 15-20% of Familial ALS (1-2% of all cases)
- 100 mutations —> Intracellular aggregate, Protein folding / degradation failure
Normal SOD1:
- 2 dimers
- each bind to Cu + Zn ion
- function of SOD1: reduction of Cu2+ —> Cu1+
—> regulate dismutation of superoxide ion into hydrogen peroxide H2O2
SOD1 mutation in Familial ALS:
Loss of physiological function
1. ***Impaired dismutase activity
Gain of toxic function
2. ***Aberrant redox chemistry: due to changes in conformation of SOD1, that leave the channel (responsible for accepting superoxide ion) able to accept larger molecules
- ***Protein instability and SOD1 aggregation (characteristic of all SOD1 mutants)
—> mitochondrial dysfunction, oxidative stress
Dynactin gene
Dynactin: responsible for ***Retrograde transport in axons (Dynein/Dynactin)
Mutation in Dynactin: ***impaired Retrograde transport
Symptoms:
- adult onset, slow progressive, early vocal cord paralysis
***Summary of HT, PD, AD, ALS
HD:
- Autosomal dominant
- Brain specific: Striatum (Caudate + Putamen)
- Loss of Medium spiny neurons (GABAergic inhibitory neurons)
- ***Huntington CAG repeats >36 —> Multiple glutamine repeats
- ***Striatal atrophy
- Mutant protein aggregation
- Chorea + Psychiatric disturbance + Cognitive impairment
PD:
- Autosomal dominant / recessive
- Substantia nigra pars compacta + Locus ceruleus
- Loss of Neuromelanin, Monoamine neurons, Monoamine —> Dopamine depletion
- **α-Synuclein, **Parkin / E3 Ubiquitin ligase (PARK1/2)
- ***Lewy bodies
- Mutant protein aggregation
- Bradykinesia, Rigidity, Resting tremor, Postural instability, Gait disturbance
AD:
- Cerebral cortex + Subcortical regions (Hippocampus) atrophy
- Loss of neurons and synapses
- **APP, **Presenilin 1/2, **ApoE, **Tau
- Neurofibrillary tangle (Hyperphosphorylated Tau): Transentorhinal region + Hippocampus
- ***Amyloid plaque: Frontal + Posterior cingulate + Posterior association cortices
- Mutant protein aggregation
- Memory loss, behavioural abnormalities
ALS:
- Autosomal dominant
- Brain + Brainstem + Spinal cord
- Motor neurons loss
- **SOD1, **Dynactin gene
- **Bunina bodies, **Hyaline bodies, ***“Skeins”
- Mutant protein aggregation
- Muscle weakness, muscular atrophy, spasticity, eventually paralysis
