Download Sensory neuropathy

Sensory Neuropathies
755 Brain in Health and Disease
Sean Sweeney
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
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)
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.
endogenous vanilloids
Examining structure of natural and synthetic
receptor agonists illustrates structural
similarities.
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
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Bradykinin, NGF bind to
metabotropic
receptors (longer signal!)
Local tissue acidosis: hallmark physiological
response to injury. Pain correlated to degree
of acidosis.
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.
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Nociceptive sensory dendrite terminal
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).
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Cox2 induction acts to reduce inhibitory
input
DREAM= inhibitory transcription factor
The Ascending Pain Pathway
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 Wall’s Gate Theory of Pain.
Pain ameliorated by mechanosensitive input. Highlights synaptic interactions in dorsal horn.
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
CENTRAL
PERIPHERAL
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:
Presynaptic: 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
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
Classification:
can be by cause: (diabetic, entrapment)
by anatomic site (intercostal neuralgia)
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, Fabry’s disease
Leukodystrophies, vitamin B deficiency, Bannworth’s 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.
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
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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
HNPP
CMT1B
CMT1C
CMT1D
CMTX1
duplication of PMP22
loss of PMP22
dominant MPZ
dominant LITAF
dominant EGR2
dominant GJB1
myelin protein 22
“
myelin protein zero
LPS-induced TNF-alpha factor
Early Growth Response 2 (with sox10!)
connexin 32
CMT4A
CMT4B1
CMT4B2
CMT4C
CMT4D
CMT4F
CMT4
recessive GDAP1
recessive MTMR2
recessive SBF2
recessive SH3TC2
recessive NDRG1
recessive PRX
recessive EGR2
ganglioside induced diff. ass. protein
myotubularin related protein 2 (phosphatase)
myotubularin related protein 13
SH3 and TPR adaptor molecule
N-myc downstream related gene
Periaxin (acts with dystroglycan/dystrophin)
Early Growth Response 2
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
Axonal Forms of CMT
Disease
Locus
Protein
CMT1F
CMT2A
CMT2B
CMT2C
CMT2D
CMT2E
CMT2F
CMT2I
CMT2J
CMT2K
NFL
mfn2A
rab7
NFL
GARS
NFL
HSPB
?
?
GDAP1
Neurofilament light chain protein
mitofusin 2A
endosomal trafficking protein Rab7
Neurofilament light chain protein
Glycyl tRNA synthetase
NFL
heat shock protein 27 (allelic to dHMN)
DI-CMT B
DI-CMT CYARS
DNM2
Theme emerges:
Demyelinating - loss of myelin
Axonal and demyelinating - axonal traffic and mitochondrial
fission/fusion (would fit with ‘length dependency’)
ganglioside induced diff. ass. protein
dynamin related protein 2
tyrosine tRNA synthetase
Enlarged mitochondria seen in many forms of neuropathy!
CMT disease Genes
PMP22, MPZ
GJB1, EGR2
MTMR2/13
CMT pathology
Schwann cells
myelinate poorly
diagnostic criteria
Reduced NCV defines
CMT1 and CMT4
Schwann cells
fail to support
axons
MFN2, Rab7a
NEFL, DMN2
Axonal transport
defects
Progressive axonal
loss
Muscle denervation
Sensory losses
Final common
pathway
Normal NCV and
reduced current
amplitudes
define CMT2
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, 3:7
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
Dominant 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?
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
conditions
e.g. Hereditary spastic paraplegia (paraplegin, HSP60), amyotrophic lateral sclerosis (SOD1)
Familial Parkinson’s disease (PINK1, parkin), Friedreich’s Ataxia (Frataxin),
mitochondrial encephalomyopthies.
Mitochondrial fission/fusion related genes prevalent in neuropathies:
GDAP1
mitofusin2
dynamin 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?
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?
a) In normal cells mitochondria transported to
dendritic extensions, soma, hillock, nodes of Ranvier
and synaptic regions.
b) In CMT, DOA, HSAN1 heterogeneity of
mitochondrial population - mitochondria with poor function
c) Mitochondrial aggregation - ineffective mitochondria
distribution, inneffective autophagic turnover?
Requirement for more mitochondria in absence of myelin?
Chen and Chan (2006) 18, 453-459
Current Opinion in Cell biology
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
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