Transcript Molecular neurobiology of disease

Parkinson’s disease
Aim
 Review quickly control of movement
 Symptoms of PD
 “Causes” of PD
 Environment
 Genetic
 Treatment
 Current
 Potential
Human Brain
Introduction
 Mechanisms of motor control of behavior
 Reflex
 Involuntary
 Voluntary
 Understanding from analysis of neural
diseases
Spinal reflex
Descending control of
motoneurons
 feedback and feedforward control
 ff
= anticipation
 primary motor cortex
 somatotopic map
 neurons
project to groups of muscles for
coordinated act
Primary motor cortex
Primary motor
cortex
 stimulation gives
movement
 fire before voluntary
movement
Role of brainstem nuclei
 Major pathway in voluntary movements
 starts
in association cortex
 caudate and putamen
 input
 globus
from substantia nigra
pallidus
 thalamus
 ends in motor cortex
Circuit
Schematic circuit
 from association (neocortex) to motor cortex
Huntington’s disease
 symptoms: faster jerky
movements
 gene for protein huntingtin
(Htt) on chromosome 4
 mutates to include CAG
(glutamine) repeats
 gene repeats increase easily
 Htt may disrupt synaptic
transmission
Neural circuit
 caudate neurons [GABA] degenerate,
 less
inhibition of thalamus
 increased excitation of cortex
 more movement
Parkinson’s disease
 symptoms: hard to initiate and maintain
movements (bradykinesia)
PD associated with DA loss
 death of dopaminergic substantia nigra
neurons
 dying cells have Lewy bodies,
 made
up of
neurofilaments
Lewy bodies
 Immunoreactive to
 a-synuclein
 ubiquitin
 a-synuclein may be
misfolded
 Adding ubiquitin to
lys marks protein for
degradation via
proteasome
Parkinson’s disease
 Loss of dopaminergic neurons
 normal:
4% per decade
 Parkinson’s: 70-80% loss
normal
substantia nigra
Parkinson’s
Changes to circuit
 more tonic inhibition of thalamus
 decreased excitation of cortex
Therapy - today
 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 [=subthalamic nuclei] stimulation
Dyskinesia
 result of >5 years LDOPA administration
 normal
 L-DOPA may be taken
up by 5-HT neurons
 use 5-HT agonists
How does DBS work ?
 stimulation ??
 inactivates
STN neurons, producing a
functional lesion 
 activates the STN output
 may
reduce burstiness
http://jn.physiology.org/cgi/content/abstract/103/2/962
Parkinson’s summary
 death of dopaminergic substantia nigra
neurons
 hard to initiate and maintain movements
(bradykinesia)
 more
tonic inhibition of thalamus
 decreased excitation of cortex
 dopaminergic therapy
What causes PD: Approaches
 epidemiology
 genetic
 chromosome
 gene
/ protein
 pharmacology
 anatomical
 post-mortem
 MRI/PET
 animal models
Parkinson’s disease
 mimic with MPTP
 1-methyl-4-phenyl-1,2,3,6-tetrahydropiridine
 metabolise to MPP+
 1-methyl-4-phenylpyridinium
 Causes ?
Animal model
 Model with MPTP  MPP+
 Neuronal damage,
 activates
microglia,
 which produce NO (iNOS),
 causes further neuronal damage
PD Causation - genetics
 Inherited disorder
 *a-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 a-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 a-synuclein
 oxidises DJ-1
 Paraquat
A model of PD
Fly models say:
 Heat shock proteins (HSP)
 a-synuclein
 stimulates
chaperone production
 Geldanamycin
 GST (glutathione – S - transferase)
 parkin
 antioxidants
 Role for rapamycin
 parkin,
pink1, LRRK2
 Mitochondrial fission/fusion affected
Mitochondrial fission/fusion
Gene therapy for the future?
 GDNF
 Glial
cell-line derived neurotrophic factor
 Open label trial ok, but …
 pump
 GAD (Glutamic Acid Decarboxylase)
 mimic
GABA in subthalamic nuclei
 AADC-2
 aromatic
L-amino-acid decarboxylase
 enzyme that synthesises DA
 parkin
lentivirus
adenovirus
Summary
 death of dopaminergic substantia nigra
neurons
 hard to initiate and maintain movements
(bradykinesia)
 more
tonic inhibition of thalamus
 decreased excitation of cortex
 mimic with MPTP (metabolise to MPP+)
 dopaminergic therapy
 potential drug therapy
 potential gene therapy
To Ponder
 Parkinson’s has
 well-defined
deficit – loss of dopaminergic
cells
 well-described pathology & behaviour
 variety of therapies
 no cure
 no known cause