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Sensory Neuropathies 755 Brain in Health and Disease Sean Sweeney.

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1 Sensory Neuropathies 755 Brain in Health and Disease Sean Sweeney


3 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 p Jeyakumar et al., (2005) Storage Solutions: Treating Lysosomal Disorders of the Brain. Nature Reviews Neuroscience Beutler, E. (2006) Lysosomal Storage Diseases: Natural History and Ethical and Economic Aspects. Molecular Genetics and Metabolism. 88,

4 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)

5 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 (!?))

6 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. MDEG = BNC1 Na+ channel (TTX insensitive) aka ‘acid sensing ion channel TREK1 = two pore K+ channel

7 endogenous vanilloids Examining structure of natural and synthetic receptor agonists illustrates structural similarities.

8 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.

9 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

10 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).

11 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

12 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

13 The Ascending Pain Pathway

14 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.

15 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.

16 Descending inputs Natural opoid peptides present in periaqueductal gray matter and spinal cord regions involved in modulation of pain: enkephalins, endorphins, dynorphins 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)

17 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 BK 1, BK 2, P2X 3 Peripheral Sensitisation: NGF, TrkA, TRPV1, Na v 1.8, PKA, PKC isoforms, CaMK IV Erk1/2, p38, JNK, IL-1ß, cPLA 2, COX2, EP1, EP3, EP4, TNF-alpha Membrane excitibility of primary afferents: Na v 1.8, Na v 1.9, 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, GABA A -R, GABA B -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

18 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…… Sprouting after peripheral nerve injury Disinhibition (after excitotoxic shock?)

19 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)

20 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.

21 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)

22 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) DiseaseLocusGene Function CMT1Aduplication of PMP22myelin protein 22 HNPPloss of PMP22 “ CMT1Bdominant MPZmyelin protein zero CMT1Cdominant LITAFLPS-induced TNF-alpha factor CMT1Ddominant EGR2Early Growth Response 2 (with sox10!) CMTX1dominant GJB1connexin 32 CMT4Arecessive GDAP1ganglioside induced diff. ass. protein CMT4B1recessive MTMR2myotubularin related protein 2 (phosphatase) CMT4B2recessive SBF2myotubularin related protein 13 CMT4Crecessive SH3TC2SH3 and TPR adaptor molecule CMT4Drecessive NDRG1N-myc downstream related gene CMT4Frecessive PRXPeriaxin (acts with dystroglycan/dystrophin) CMT4recessive EGR2Early Growth Response 2

23 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 A∂ fibres are myelinated

24 Axonal Forms of CMT DiseaseLocusProtein CMT1FNFLNeurofilament light chain protein CMT2Amfn2Amitofusin 2A CMT2Brab7endosomal trafficking protein Rab7 CMT2CNFL Neurofilament light chain protein CMT2DGARSGlycyl tRNA synthetase CMT2ENFLNFL CMT2FHSPBheat shock protein 27 (allelic to dHMN) CMT2I? CMT2J? CMT2KGDAP1 ganglioside induced diff. ass. protein DI-CMT BDNM2dynamin related protein 2 DI-CMT CYARStyrosine 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!

25 CMT disease GenesCMT pathologydiagnostic criteria PMP22, MPZ GJB1, EGR2 MTMR2/13 Schwann cells myelinate poorly 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 Normal NCV and reduced current amplitudes define CMT2 Final common pathway

26 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

27 Hereditary, Sensory and Autonomic Neuropathy type 1 (HSAN1) Contd. Mutations mapped to SPTLC1 gene. (Dawkins et al., (2001) Nat. Genet. 27; 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?

28 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.

29 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?

30 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?Chen and Chan (2006) 18, Current Opinion in Cell biology Requirement for more mitochondria in absence of myelin? Mitochondrial fission and fusion and neurological function

31 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

32 Reading Material: Julius, D. and Basbaum, A.I. (2001) Molecular mechanisms of nociception. Nature 413, 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, Scholz, J. and Woolf, C.J. (2002) Can we conquer pain? Nature Neuroscience. 5, Detmer, S.A. and Chan, D.C. (2007) Functions and Dysfunctions of mitochondrial Dynamics. Nature Reviews Molecular Cellular Biology

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