725 - Molecular neurobiology of disease

Parkinson’s disease Schizophrenia Alzheimer’s disease

Reference List

Approaches epidemiology genetic

chromosome gene / protein

pharmacology anatomical

post-mortem MRI/PET

animal models

Human Brain cut vertically down

midline

Parkinson’s disease Loss of dopaminergic neurons

normal: 4% per decade Parkinson’s: 70-80% loss

normal Parkinson’s

substantia nigra

Symptoms Hard to initiate

movement Interaction of

substantia nigra with cortex

see 746 lecture 6

Therapy L-DOPA

cross blood-brain barrier dopamine agonists MAO-B inhibitors (selegiline = deprenyl) cell replacement

fetal midbrain transplants pigs carotid body stem cells

deep brain [=thalamus] stimulation

Animal model Model with MPTP MPP+

Neuronal damage, activates microglia, which produce NO (iNOS), causes further neuronal damage

MPTP (1-methyl-4-phenyl -1,2,3,6-tetrahydropyridine)

MPP 1-Methyl-4-phenylpyridinium

Causation Inherited disorder

-synuclein (folds SNAREs) Parkin (E3 ubiquitin ligase) DJ-1 (stress response chaperone) PINK-1 (mitochondrial protein kinase) *LRRK2 (another ?mitochondrial kinase) It is not clear why mutations in -

synuclein, or parkin or [] genes cause nigral dopaminergic cell death in familial PD [Le W & Appel SH (2004)]

*dominant – others are recessive

Causation Environmental factors too

Rotenone fish poison blocks mitochondrial function upregulates -synuclein oxidises DJ-1

Paraquat

One model

inhibitors of parkin

Another model

Summary Parkinson’s has

well-defined deficit – loss of dopaminergic cells

well-described pathology & behaviour variety of therapies no cure no known cause

Schizophrenia Positive (hallucinations) & negative

symptoms (asociality) possibly several illnesses seasonal highly inherited

Developmental disease genetic cause :

DISC1 or a chromosome translocation

caused by failure of neurons to migrate ?

red shows areas less in Sc

Dopamine hypothesis positive symptoms respond to

treatment negative symptoms do not respond to

treatment DA antagonists

Chlorpromazine side effects, e.g. Parkinsonism,

constipation Haloperidol

D2 (+D3, D4 +5-HT2A) blocker

Newer drugs e.g. clozapine dopamine D2 receptors and 5-HT action

D2 receptor block is key point e.g. mouse model

-ve symptoms from DA in prefrontal cortex

5-HT action helps -ve symptoms NMDA (glutamate) receptors blocked by

phencyclidine, relieves many symptoms

Depression 5-HT (=serotonin)

main treatment is with uptake inhibitors

SSRI eg Prozac Noradrenaline

also selective re-uptake inhibitors

PFC: pre-frontal cortex

Summary so far ethical issues “impede” research animal models hard to interpret key concept: neural diseases identified

with cellular / molecular deficit disease related to change in specific

neurotransmitter complexity of CNS leads to side effects

Dementia Reduction of brain volume and cells

with age Dementia increases with age

at 65, 11% of USA had dementia 70% of dementia is Alzheimer’s 15% from strokes

at 85, 47% affected Early onset Alzheimer’s inherited

<1% of cases

Alois Alzheimer On November 3, 1906, Alois Alzheimer

gave a lecture to the Meeting of the Psychiatrists of South West Germany, presenting the neuropathological and clinical description of the features of one of his cases, Auguste D., who had died of a dementing illness at the age of 55,

Alzheimer’s Symptoms Forgetfulness untidiness confusion less movement storage of new memory reduced finally loss of bodily function

Neuroanatomy cortex very reduced

normal Alzheimer

Neuroanatomy cortex reduced - note gaps between

folds

Neurodegeneration brains feature

plaques(A =-amyloid)

tangles(tau)

Neurofibrillary tangles micrograph drawing by Alois

Alzheimer

Development of tau

Amyloid hypothesis Down’s syndrome leads to AD by 40

linked to chromosome 21 Positional cloning identified: amyloid- (A) peptide 40-42 amino

acids families with mutations in APP

670 / 692 / 716 & 717 amyloid toxic to cultures

Presenilins Familial early onset dominant AD

linked to mutations on chromosomes 14 & 1 presenilin I : mutations lead to onset at

age 28 presenilin II : second homologous gene

mutations are in regions conserved between PSI

and PSII associated with AD lead to increased A production

Presenilins code for two secretases and involved in processing APP

secretase now called ADAM secretase called BACE

Proteolysis of APPNormal

amyloidogenic

APP

Proteolysis of A In non-familial AD, plaques caused not

by production of A but by failure to degrade it

Little evidence for increased production of A peptide

maybe normally degraded quickly half life 1-2 hr

tangles resistant to degradation enzymes:

neprilysin & insulin-degrading-enzyme

Neprilysin

Neprilysin knockout mice have more A

how does faulty -amyloid lead to tangles of tau?

tau is hyperphosphorylated

GSK-3 glycogen synthase kinase

Major problem

More direct interaction? tau and A form complexes GSK-3 phosphorylates tau in complex

tau A Ais extracellular

in neurons

tau v A AD has both tau and A other diseases have just tangles of tau

Apolipoprotein E Another family gene for late onset of

AD produces Apolipoprotein E

Apolipoprotein E - cont receptor (LRP) expressed in astrocytes normal role is in cholesterol transport may aid in clearance of -amyloid from

brain to blood mutations disrupt clearance

Oxidative stress main function of -amyloid may be to

protect cells from reactive Oxygen radicals

damage to mitochondria leads to *OH shortage of energy (or oxygen)

increases likelihood of AD through high [Ca]

metal ions might affect build up of -amyloid

Therapy ?? cholinergic therapy secretase blockers relief of oxidative stress Apolipoprotein therapy stem cells for replacement vaccination ginko biloba

Cholinergic hypothesis cholinergic neurones in basal forebrain

project to cortex and hippocampus muscarinic antagonist, (M1),

pirenzipine, causes memory loss in hippocampus

agonists, e.g. physostigmine, improve memory

But other systems interact

Cholinergic therapy Cholinesterase inhibitors – delay

symptoms Tacrine: allosteric – 1993 (toxic in liver) Donepezil; mixed binding

Try Cholinergic agonist M2 on basal ganglia and intestine

Depletion of M1 receptors? M1 and M3 receptors in hippocampus

Drug trials discontinued

Summary of AD Full mechanism not known

amyloid hypothesis well – established role of tau also established role for glia and neurons

No one effective treatment cholinotherapy promising ?

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