Disorders of nervous system Flashcards
What is the definition of a neurodegenerative disease?
Disorder in which particular neurons degenerate leading to loss of function of that region of the central or peripheral nervous system
What are some neurodegenerative diseases?
Alzheimer’s
Parkinson’s
Huntington’s
Sclerosis
What are the main neurons lost in Alzheimer’s?
Cholinergic neurons
What is the first part of the brain usually affected by Alzheimers?
Hippocampus and then spreads to frontal lobe (communication) and parietal (orientation)
What are plaques of Alzheimers made of ?
extracellular deposits of degenerating nerve processes and a core of insoluble beta-amyloid proteins
What are neurofibrillary tangles?
In Alzheimers disease, they are found in cell bodies and axons and are composed of hyperphosphorylated protein tau, which is involved in assembly of microtubules
What are the genetic factors involved in Alzheimers ?
Mutations of the genes encoding amyloid precursor protein (APP) and presenilin (involved in processing amyloid )
What are possible environmental factors involved in Alzheimers?
high levels of aluminium in soil
Where is APP usually found?
Membrane of neurons
What enzyme cleaves APP into fragments?
Secretase enzyme (alpha,beta,gamma). Presenilin is catalytic component of gamma-secretase
What fragment of APP is particularly toxic to neurons?
A(beta)42
What are the current drugs used for Alzheimers?
Acetylcholineesterase inhibitors that prevent breakdown of ACh, or ACh receptor agonist that mimic ACh and alleviate symptoms
What are future possibilities for Alzheimers treatment?
Inhibition of secretase enzyme
Antibody-base drugs designed to target toxic Abeta
Vaccine to improve immunity to toxic Abeta
Stem cells to replace lost neurons
What causes Parkinson’s disease?
The degeneration of dopaminergic neutrons of the nigrostriatal pathway
What is one of the features of Parkinson’s?
The accumulation of dense deposits (Lewy bodies) in the nigrostriatal neurons that impair their function or destroy them
What is the nigrostriatal pathway?
Neurons that project from the substantia ingrate to the striatum (basal ganglia)
What could be an environmental factor for Parkinson’s?
Exposure to MPTP which is oxidised by the monoamine oxidase found in dopaminergic neurons, into MPP+ . This then binds to Neuromelanin and inhibits etc killing the cell
What are the genes involved in Parkinson’s?
SNCA gene (park1) which encodes alpha-synuclein and PARK2 gene that encodes the protein parkin
What is the role of alpha-synuclein ?
It is a nerve terminal protein and a toxic form of it is found in Lewy bodies
What is the role of Parkin?
An enzyme component of ubiquitin-proteasome pathway responsible for removal of damaged proteins
What are the treatments for Parkinson’s?
- L-DOPA , precursor of dopamine
- Inhibitors of enzyme monoamine oxidase which degrades dopamine
- DEEP BRAIN STIMULATION: surgical procedure where electrons are implanted in the brain and connected to a stimulator places somewhere else in the body. These impulses override the abnormal electrical signals caused by the disease
What is the most common demyelinating disorder?
Multiple sclerosis
Is MS acquired or inherited?
Acquired
What are some possible causes of MS?
- Infectious agent: Epstein-Barr virus mostly
- Immune-mediated: antibodies produced against myelin components (molecular mimicry)
- Genetic Factors: mostly genes involved in MHC
How is MS diagnosed?
- Nerve conduction test (record speed of electrical conduction)
- Sampling of CSF by lumbar puncture for presence of white blood cells or antibodies
- Magnetic Resonance Imaging to look for abnormalities and scarring in white matter
How is MS treated?
Drugs like β-interferons that alleviate symptoms and progression by acting at the Level of immune system
Exercise, physiotherapy and diet
Is Guillan-Barrè syndrome acute or chronic?
Acute
What is another name for Guillan-Barrè syndrome ?
Acute inflammatory demyelinating polyneuropathy
What neurons does Guillan-Barrè affect?
Somatic motor (paralysis and respiratory problems)
Sensory neurons (loss of sensation)
Autonomic neurons ( blood pressure and cardiac arrhythmia)
How does Guillan-Barrè happen?
When antibodies triggered by a viral infection attack components of Schwann cell myelin
What is a treatment for Guillan-Barrè ?
Immunoglobulins intravenously and plasmapheresis (plasma exchange)
Is Charcot-Marie-Tooth Disease inherited ?
Yes
In which way is CMT usually inherited?
Autosomal (dom/rec.) in 80-90% of cases
What is the main gene affected in autosomal cases of CMT?
Peripheral myelin protein-22 (PMP-22) involved in development and maintenance of Schwann cell myelin
Rare cases due to mutations in myelin protein zero (P0) gene which encodes an adhesion molecule important for compaction of PNS myelin
What is the main gene affected in cases of CMTX?
Mutation in gene connexion 32 which encodes the channel proteins of gap junctions
Where is Cx32 found?
Schwann cells
What does Cx32 do?
Forms reflexive gap junctions between the layers of myelin membrane surrounding peripheral axons
What are symptoms of myasthenia disorders?
Weakness and fatiguability affecting ocular, facial, bulbar, respiratory and limb muscles
How do myasthenic disorders arise?
From defects in any of the components of synaptic transmission and may arise from autoimmune or genetic basis
Two examples of autoimmune myasthenic disorders?
Myasthenia gravis (MG) and Lambert-Eaton Myasthenia (LEMS)
What happens in MG?
Auto-antibodies attack protein subunits of nicotinic ACh receptor
Is MG presynaptic or postsynaptic defect?
Postsynaptic
How does MG affect nicotinic ACh receptor?
Autoantibodies either block transmitter binding,
increase the rate of receptor degradation
or destroy the postsynaptic membrane leading to cell lysis
What happens in LEMS?
Antibodies attack voltage gated Ca++ channels in the motor neuron presynaptic terminal, reducing ACh release as Ca++ is trigger for exocytosis
Is LEMS presynaptic or postsynaptic defect?
Presynaptic
Examples of Congenital myasthenic syndromes
- Ach Receptor deficiency
- Congenital myasthenic syndrome with Episodic apnea (CMSEA)
- End plate Acetylcholinesterase deficiency
What happens in ACh receptor deficiency ?
Mutations in genes that encode subunits of nicotinic ACh receptor leading to fewer receptors or with altered properties (POSTSYNAPTIC)
What happens in Congenital myasthenic syndrome with Episodic apnea (CMSEA)?
Mutations in choline acetyltransferase, the ACh synthetic enzyme leading to insufficient production of neurotransmitters (PRESYNAPTIC)
What happens in End Plate Acetylcholinesterase Deficiency?
Mutations in acetylcholinetransfferase, the ACh degradative enzyme leading to insufficient production of neurotransmitter (SYNAPTIC DEFECT)
What can LEMS be associated with?
Lung cancer or other cancers because of cell mimicry
What are some symptoms of CMT?
- motor deficits (weakness of leg, foot and hand muscles)
- sensory loss ( unable to perceive temperature, pain..)
