Sensory Neuropathies

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Sensory Neuropathies 755 Brain in Health and
Disease Sean Sweeney
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(No Transcript)
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Reading Material for the Lysosomal Storage
Disease lecture Haltia, M. (2006) The Neuronal
ceroid-lipofuscinoses from past to present.
Biochim. Biophys. Acta - Molecular Basis of
Disease Vol. 1762 p850-856 Jeyakumar et al.,
(2005) Storage Solutions Treating
Lysosomal Disorders of the Brain. Nature Reviews
Neuroscience. 6. 1-12 Beutler, E. (2006)
Lysosomal Storage Diseases Natural History and
Ethical and Economic Aspects. Molecular Genetics
and Metabolism. 88, 208-215
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Pain Sensation of pain nociception (latin
nocere - to hurt) Role to alert to impending
injury or to trigger appropriate protective
response Transduction of noxious stimuli
(thermoceptive pain, mechanoreceptive pain) BUT
ALSO cognitive and emotional processing Sensory
modality, in PNS, CNS and ANS A class of neuron
(global?) proposed by Sherrington, activated by
stimuli capable of causing tissue
damage. (Sherrington, C.S. The Integrative Action
of the Nervous System (Scribner, New York, 1906)
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Nociception mediated by diverse sensory neurons
in periphery. (innervating the skin) majority of
this lecture. Others Tissues Corneal afferents
sensitive to capsaicin and inflammatory
mediators BUT, mostly pain produced in response
to small stimuli. Teeth any stimuli produces
pain. Visceral Pain poorly localised, deep and
dull. Tissue damage not required, other stimuli
(distension) Nociception is a strong stimulus
with resultant strong responses Requires
modulation (sensitisation) at cellular, neuronal
and circuit level. (Psychosomatic (!?))
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MDEG BNC1 Na channel (TTX insensitive) aka
acid sensing ion channel TREK1 two pore K
channel
Nociceptive neurons arise in the Dorsal Root
Ganglion (DRG) Noxious stimuli transduced into
neuronal activity by molecular triggers
responsive to various stimuli 1st response,
reflex withdrawal, followed by higher order
behavioural responses.
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endogenous vanilloids
Examining structure of natural and synthetic
receptor agonists illustrates structural similari
ties.
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The inflammatory soup components released in
response to damage or inflammation potentiate or
maintain the initial nociceptive
signal. Protons, ATP, neurotransmitters alter
neuronal excitability directly Bradykinin, NGF
bind to metabotropic receptors (longer signal!)
Local tissue acidosis hallmark
physiological response to injury. Pain correlated
to degree of acidosis.
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Nociceptive sensory neurons respond to stimuli
with subcellular modulation threshold for
stimulation is reduced. (hyperalgesia, peripheral
sensitisation) Modification of TRPV1 (and others)
results in lowered threshold activation.
Nociceptive sensory dendrite terminal
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Damage to nociceptor neurons increases in
transcription or trafficking of Na channels with
a reduction in K channels results in
spontaneous or ectopic activation. Long term
activity of nociceptor neurons results in longer
term changes in activity mediated by
transcription (mediated also by cytokines)
leads to long term changes in activity (positive
and negative).
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The circuitry primary sensory neurons in the
DRG project dendrites to peripheral
tissue. Major types C Fibres (SLOW!!) A?
Fibres (FAST!!) Morphological and
physiological differences Diameter linked to
speed of conduction
A?Fibres ca. 20m/s C Fibres ca. 2m/s (ALL
relatively slow, but C much slower than A?) A?
two classes, mechanosensitive and
mechanothermal C polymodal
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Sensory integration in the dorsal horn is subject
to activity dependent central sensitisation
(a) and longer term transcription
dependent central sensitisation (b). Cox2
induction acts to reduce inhibitory input DREAM
inhibitory transcription factor
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The Ascending Pain Pathway
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Secondary neurons and processing by higher order
relays of neurons modulation can occur at
higher levels of communication between second
order neurons or feed down through descending
inhibitory pathways to affect local circuits in
made by the primary neurons. Descending system
alters responses of reflex circuits.
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Modulation of nociceptive response at 1st point
of sensory integration (in dorsal horn)
Melzack and Walls Gate Theory of Pain. Pain
ameliorated by mechanosensitive input. Highlights
synaptic interactions in dorsal horn.
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Descending inputs
Enkephalin receptors on presynaptic site of
nociceptive neuron responds to enkephalin to
inhibit release of Glutamate and substance
P. (enkephalin projections also controled by
descending projections)
Natural opoid peptides present in periaqueductal
gray matter and spinal cord regions involved in
modulation of pain enkephalins, endorphins,
dynorphins
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Many points of control have evolved Complexity
offers many alternative strategies and targets
for therapeutic intervention
Transduction TRPV1, TRPV2, TRPV3, TRPM8, ASIC,
DRASIC, MDEG, TREK-1 BK1, BK2, P2X3 Peripheral
Sensitisation NGF, TrkA, TRPV1, Nav1.8, PKA, PKC
isoforms, CaMK IV Erk1/2, p38, JNK, IL-1ß,
cPLA2, COX2, EP1, EP3, EP4, TNF-alpha Membrane
excitibility of primary afferents Nav1.8,
Nav1.9, K channel Synaptic Transmission Presyn
aptic VGCC, adenosine-R, (mGluR) Postsynaptic
AMPA/kainate-R, NMDA-R, mGlu-R, NK1, Nav1.3, K
channels Central Inhibition GABA, GABAA-R,
GABAB-R, Glycine-R, NE, 5HT, opoid
receptors CB1 Signal Transduction PKA, PKC
isoforms, ERK, p38, JNK Gene Expression c-fos,
c-jun, CREB, DREAM
PERIPHERAL
CENTRAL
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Pain is a strong stimulus. Many points of
control have evolved, therefore many points of
control can become defective. Gives rise to the
generation of non-nociceptor mediated pain For
example
Disinhibition (after excitotoxic shock?)
Sprouting after peripheral nerve injury
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Disease related Peripheral Pain Definitions and
classification Neuralgia Pain in the
distribution of a nerve or nerves. The term
should be used primarily to refer to non
paroxysmal pains. Neuropathy A disturbance of
function or a pathologic change in the
nerves. mononeuropathy involving a single
nerve mononeuropathy multiplex involving several
nerves Polyneuropathy involving symmetric or
bilateral nerves neuritis special type of
neuropathy with an inflammatory
process. allodynia condition where normally
non-painful stimuli become painful Classificatio
n can be by cause (diabetic, entrapment) by
anatomic site (intercostal neuralgia)
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Etiology based classification of peripheral
neuropathies Focal or multifocal lesions of
PNS Entrapment syndromes, Phantom limb, stump
pain, Post-traumatic neuralgia Postherpetic
neuralgia (shingles), Diabetic mononeuropathy,
Ischemic neuropathy Polyarteritis
nodosa Generalised Lesions of the PNS
(polyneuropathies) Diabetes mellitus, Alcohol,
Plasmocytoma, HIV neuropathy, HSNs, Fabrys
disease Leukodystrophies, vitamin B deficiency,
Bannworths syndrome(neuroborreliosis) Toxic
neuropathies arsenic, thallium, chloramphenicol,
vinca alkaloids, gold, isoniazid, nitrofurantoin
(antibiotic), metronidazole (anti-protist) Lesions
of the CNS spinal cord injury, brain infarction
(esp. thalamus and brainstem), spinal
infarction syringomyelia, MS Complex neuropathic
disorders Complex regional pain syndromes type I
and II (reflex sympathetic dystrophy, causalgia).
Demyelinating neuropathies.
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Charcot-Marie-Tooth Disease (aka peroneal
muscular atrophy and hereditary motor sensory
neuropathy) Most commonly inherited neurological
disorder estimated 2.6million affected worldwide.
Discovered 1886 Jean-Martin Charcot, Pierre
Marie and Howard Henry Tooth Sensory neuropathy
with progressive loss of use of feet and
hands Nerves to extremities degenerate with
muscle weakness (and degeneration) through loss
stimulation. Hammer toes, foot drop (loss of
tendon/muscle tension balance). Diagnosed with
electrophysiology (conduction velocity tests)
followed by genetic testing Bilateral and
length dependent. No current cure (therapy,
physical and occupational) Does not affect life
expectancy No ethnic association (except CMT4 -
Spanish gypsies)
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CMT 18 types can be identified by genetic
testing Two main classifications CMT type 1 -
demyelinating disease CMT type 2 - diminished
responses in sensory neurons (six
subtypes) Demyelinating CMT (types 1 and
4) Disease Locus Gene Function CMT1A duplica
tion of PMP22 myelin protein 22 HNPP loss of
PMP22 CMT1B dominant MPZ myelin protein
zero CMT1C dominant LITAF LPS-induced TNF-alpha
factor CMT1D dominant EGR2 Early Growth
Response 2 (with sox10!) CMTX1 dominant
GJB1 connexin 32 CMT4A recessive
GDAP1 ganglioside induced diff. ass.
protein CMT4B1 recessive MTMR2 myotubularin
related protein 2 (phosphatase) CMT4B2 recessive
SBF2 myotubularin related protein
13 CMT4C recessive SH3TC2 SH3 and TPR adaptor
molecule CMT4D recessive NDRG1 N-myc downstream
related gene CMT4F recessive PRX Periaxin (acts
with dystroglycan/dystrophin) CMT4 recessive
EGR2 Early Growth Response 2
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A? fibres are myelinated
Presence of myelin sheath critical for nerve
conduction velocity. Loss of myelin sheath
results in reduced and less efficient
transmission of action potentials Also loss of
myelin can result in spontaneous production of
action potentials
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Axonal Forms of CMT Disease Locus Protein CMT1
F NFL Neurofilament light chain
protein CMT2A mfn2A mitofusin
2A CMT2B rab7 endosomal trafficking protein
Rab7 CMT2C NFL Neurofilament light chain
protein CMT2D GARS Glycyl tRNA
synthetase CMT2E NFL NFL CMT2F HSPB heat
shock protein 27 (allelic to dHMN) CMT2I ? CMT2J
? CMT2K GDAP1 ganglioside induced diff. ass.
protein DI-CMT B DNM2 dynamin related protein
2 DI-CMT C YARS tyrosine tRNA synthetase Theme
emerges Demyelinating - loss of myelin Axonal
and demyelinating - axonal traffic and
mitochondrial fission/fusion (would fit with
length dependency) Enlarged mitochondria
seen in many forms of neuropathy!
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CMT disease Genes CMT pathology diagnostic
criteria
PMP22, MPZ GJB1, EGR2 MTMR2/13
Schwann cells myelinate poorly
Reduced NCV defines CMT1 and CMT4
Schwann cells fail to support axons
Final common pathway
MFN2, Rab7a NEFL, DMN2
Axonal transport defects
Normal NCV and reduced current amplitudes define
CMT2
Progressive axonal loss
Muscle denervation Sensory losses
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Hereditary, Sensory and Autonomic Neuropathy type
1 (HSAN1) synonyms Hereditary sensory
neuropathy type 1 (HSN1) Charcot-Marie Tooth type
2B syndrome (HMSN 2B) Hereditory sensory
radicular neuropathy Thevenard syndrome Familial
trophoneurosis Mal perforant du pied Familial
syringomyelia Slowly progressive characterised
by distal sensory loss, occasional lancinating
pain, autonomic disturbance (often seen in
sweating), juvenile or adult onset. Variable
motor involvement, slow healing wounds,
chronic skin ulcers. Often results in amputation
(of legs). autosomal dominant inheritance,
(types II to V are recessive) clinically and
genetically heterogenous Found in occasional
families (England, founder populations in Canada
and Austrailia, also China) Sural nerve biopsy
reveals demyelination (Auer-Grumbach (2008)
Orphanet Journal of Rare Diseases, 37
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Hereditary, Sensory and Autonomic Neuropathy type
1 (HSAN1) Contd. Mutations mapped to SPTLC1
gene. (Dawkins et al., (2001) Nat. Genet. 27
309-312 SPTLC1 a subunit of the Serine
palmitoyl-transferase (SPT)enzyme (spt1 and spt2
comprise the heterodimer). SPT a
pyridoxal-5-phosphate dependent enzyme, 1st step
in the de novo synthesis of sphingolipids Dominan
t mutation suggests C133W/Y creates a dominant
negative (?)
Structure from sphingomonas paucimobilis (a
homodimer) would suggest C133W/Y would be
dominantly inactivating
Why would a loss of sphingolipid synthesis
particularly affect the sensory system in a
length dependent manner?
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Loss of spt2 (second subunit of SPT) in
Drosophila results in enlarged mitochondria
in neuronal tissue
Mitochondria in neurons are essential for ATP
production, but also for Ca2 homeostasis and
apoptosis Mitochondrial dysfunction predominant
in many neuropathic and neurodegenerative conditio
ns e.g. Hereditary spastic paraplegia
(paraplegin, HSP60), amyotrophic lateral
sclerosis (SOD1) Familial Parkinsons disease
(PINK1, parkin), Friedreichs Ataxia
(Frataxin), mitochondrial encephalomyopthies.
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Mitochondrial fission/fusion related genes
prevalent in neuropathies GDAP1 mitofusin2 dynam
in related protein 2 Enlarged mitochondria
present in HSAN1 Diabetic Sensory
Neuropathy How important is mitochondrial
fission/fusion to sensory dendritic function?
Mitochondria Mitochondria highly dynamic and
undergo continual fusion and fission This
controls overall morphology AND proper function
(allows turnover via autophagy (rab7?)).
opa-1 dominant mutation in Dominant Optic
Atrophy (a sensory structure)
Fusion Mfns mediate tethering of pre-fusogenic
mitochondria (Mfns are GTPases) OPA1 on inner
membrane Fission Fis1 cover outer membrane Drp
coalesces in spots of constriction GDAP1 promotes
fission (on outer membrane) Ceramide?
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Mitochondrial fission and fusion and neurological
function

• Do fusion/fission defects affect respiratory
• capacity? (usually only seen with complete arrest
• of fusion)
• Do fusion/fission defects alter calcium
• homeostasis?
• Do fusion/fission defects alter mitochondrial
• transport along axons? (mitochondrial
• aggregation?)
• Do fusion/fission defects alter responses to
• apoptosis?
• In normal cells mitochondria transported to
• dendritic extensions, soma, hillock, nodes of
  Ranvier
• and synaptic regions.
• In CMT, DOA, HSAN1 heterogeneity of
• mitochondrial population - mitochondria with poor
  function

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Summary Pain is a powerful stimuli and
perception is regulated at many levels,
molecular, cellular, synaptic and systems. The
complexity of pain perception is reflected in the
variety of diseases where pain is a prominent
outcome (neuropathies, neuralgias, neuritis
etc). The genetic condition Charcot-Marie Tooth
disease results from the loss of myelin in
peripheral nerves and also loss of mitochondrial
fission/fusion dynamics (other conditions may
share this etiology) Mitochondrial
fission/fusion is essential to neuronal
function though the mechanism remains unlcear
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Reading Material Julius, D. and Basbaum, A.I.
(2001) Molecular mechanisms of nociception.
Nature 413, 203- 210 Nave, K.-A., Sereda, M.W.
and Ehrenreich (2007) Mechanisms of Disease
inherited Demyelinating neuropathies - from basic
to clinical research. Nature Cilincal
Practice Neurology 3, 453-464 Scholz, J. and
Woolf, C.J. (2002) Can we conquer pain? Nature
Neuroscience. 5, 1062- 1067 Detmer, S.A. and
Chan, D.C. (2007) Functions and Dysfunctions of
mitochondrial Dynamics. Nature Reviews Molecular
Cellular Biology. 8. 870-879