Discussion about the historical aspects of axoplasmic flow, the mechanisms, microtubule motors, and applications in neurological diseases and therapeutics.
2. Road Map for the Session
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Introduction and need for this discussion
Historical aspects and the pioneers
Characterization of the types of axoplasmic flow
The molecular “motors”
Integration of concepts
Clinical utilization of the information – pathogenesis
Clinical utilization of the information – therapeutics
• Further reading
3. Road Map for the Session
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Introduction and need for this discussion
Historical aspects and the pioneers
Characterization of the types of axoplasmic flow
The molecular “motors”
Integration of concepts
Clinical utilization of the information – pathogenesis
Clinical utilization of the information – therapeutics
• Further reading
8. Road Map for the Session
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Introduction and need for this discussion
Historical aspects and the pioneers
Characterization of the types of axoplasmic flow
The molecular “motors”
Integration of concepts
Clinical utilization of the information – pathogenesis
Clinical utilization of the information – therapeutics
• Further reading
11. Initial Response
Jordi Floch, Founder
AAN –
“Thank God! What
do you think the
nervous system is, a
plumbing system ?”
12. Road Map for the Session
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Introduction and need for this discussion
Historical aspects and the pioneers
Characterization of the types of axoplasmic flow
The molecular “motors”
Integration of concepts
Clinical utilization of the information – pathogenesis
Clinical utilization of the information – therapeutics
• Further reading
13. Advent of electron microscopy
• Late 1960’s
• Characterization of Sub cellular structure of
Neuron
• Absence of Golgi apparatus, RER and
centromere from Axon
• Presence of cytoskeletal proteins, vesicles,
neurofilaments and neurotubules in axon
31. Classification of Axonal Flow
• Slow Transport
– Antegrade, 0.1 to 4 mm/day
• Fast Transport
– Antegrade at up to 400 mm/day
– Retrograde at 40-400 mm/day
43. Road Map for the Session
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Introduction and need for this discussion
Historical aspects and the pioneers
Characterization of the types of axoplasmic flow
The molecular “motors”
Integration of concepts
Clinical utilization of the information – pathogenesis
Clinical utilization of the information – therapeutics
• Further reading
47. Kinesins
Kinesins are a large family of proteins with diverse
structures. Mammalian cells have at least 40 different
kinesin genes.
The best studied is referred to as conventional kinesin,
kinesin I, or simply kinesin.
Some are referred to as kinesin-related proteins (KRPs).
Kinesin I has a structure analogous to but distinct from
that of myosin.
There are 2 copies each of a heavy chain and a light chain.
53. Rafts and cytoskeletal proteins
as new cargoes
Molecular motors: from one motor many tails to one motor many tales.
Lawrence S.B. Goldstein Trends in Cell Biology, 2001, 11:12:477-482
58. Fast Axonal Transport: 100-400 mm/day
Purpose: Transport organelles such as mitochondira and vesicles
carrying SV and plasma membrane proteins to the nerve terminal.
Also retrograde movement of vesicles containing neurotrophic factors
back to the cell body.
61. Road Map for the Session
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Introduction and need for this discussion
Historical aspects and the pioneers
Characterization of the types of axoplasmic flow
The molecular “motors”
Integration of concepts
Clinical utilization of the information – pathogenesis
Clinical utilization of the information – therapeutics
• Further reading
62.
63. Summary for axoplasmic transport
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Necessity
Types
Kinesins
Dyenins
• Summation
• Need for this information !!!
64. Road Map for the Session
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Introduction and need for this discussion
Historical aspects and the pioneers
Characterization of the types of axoplasmic flow
The molecular “motors”
Integration of concepts
Clinical utilization of the information – pathogenesis
Clinical utilization of the information – therapeutics
• Further reading
65.
66. •
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Axonopathy and transport deficits early in the pathogenesis of
Alzheimer's disease. Stokin GB, Lillo C, Falzone TL, Brusch RG,
Rockenstein E, Mount SL, Raman R, Davies P, Masliah E, Williams DS, Goldstein
LS Science 2005 Feb 25; 307(5713):1282-8
67. •
Selective vulnerability and pruning of phasic motoneuron axons in
motoneuron
disease alleviated by CNTF. Pun S, Santos AF, Saxena S, Xu L, Caroni PNat Neurosci
2006 Mar 9(3):408-19
• Charcot-Marie-Tooth disease type 2A caused by mutation in a
microtubule motor KIF1Bbeta. Zhao C, Takita J, Tanaka Y, Setou M, Nakagawa T, Takeda S,
Yang HW, Terada S, Nakata T, Takei Y, Saito M, Tsuji S, Hayashi Y, Hirokawa NCell 2001
Jun 1 105(5):587-97
68. •
1-Methyl-4-phenylpyridinium induces synaptic dysfunction through a pathway involving
caspase and PKCdelta enzymatic activities. Proc Natl Acad Sci U S A. 2007 Feb
13;104(7):2437-41 – Model for
neurodegenration
69. •
Jones LG, Prins J, Park S, Walton JP, Luebke AE, Lurie DI.
•
beading, and temporal processing deficits within the murine auditory brainstem.
J Comp Neurol. 2008 Feb 20;506(6):1003-17.
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Pan T, Kondo S, Le W, Jankovic J.
• Lead exposure during development results in increased neurofilament phosphorylation, neuritic
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The role of autophagy-lysosome pathway in neurodegeneration associated with
disease.
•
Brain. 2008 Jan 10; [Epub ahead of print]
Parkinson's
70. •
Inflammation, demyelization,neurodegeneration, and neuroprotection in the pathogenesis of
mutliple sclerosis. Peterson, Lisa K. , Fujinami, Robert S.
•
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Journal Neuroimmunology 184 (2007): 37-44
multiple sclerosis: Role in symptom production,
Sodium channels and
damage and therapy. Smith, Kenneth J.
Brain Pathology 2007 Apr;17(2):230-42.
71. •
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Proteomic analysis of rat cortical neurons after
fluoxetine (FLUX) treatment
Long-Term Impairment of Anterograde Axonal Transport Along Fiber Projections Originating in
the Rostral Raphe Nuclei After Treatment With Fenfluramine or
Methylenedioxymethamphetamine (MDMA)
73. Road Map for the Session
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Introduction and need for this discussion
Historical aspects and the pioneers
Characterization of the types of axoplasmic flow
The molecular “motors”
Integration of concepts
Clinical utilization of the information – pathogenesis
Clinical utilization of the information – therapeutics
• Further reading
74.
75.
76.
77. Road Map for the Session
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Introduction and need for this discussion
Historical aspects and the pioneers
Characterization of the types of axoplasmic flow
The molecular “motors”
Integration of concepts
Clinical utilization of the information – pathogenesis
Clinical utilization of the information – therapeutics
• Further reading
Rabies does not wait, replicate in the cell body immediately and come back..
Figure 4 | Kinesin superfamily proteins (KIFs) bind to cargoes through adaptor or
scaffolding protein complexes. a | KIF13A binds to β1-adaptin of the AP1 (adaptor protein 1)
adaptor complex and the AP1 adaptor complex binds to the mannose-6-phosphate receptor
(M6PR)80. The AP1 adaptor complex comprises the β1-, γ-, 1- and δ1-adaptin subunits.
β1-adaptin has three domains — trunk, hinge and ear — and the carboxy (C)-terminal tail of
KIF13A binds to the ear domain. b | the C-terminal tail of KIF17 binds to one of the PDZ domains
of LIN10 (Munc18-interacting protein, MINT1)65. LIN10, LIN2 (CASK, calcium/calmodulin
dependent serine protein kinase) and LIN7 (VELIS, vertebrate LIN7 homologue/MALS,
mammalian LIN7 protein), all have PDZ domains and interact through regions other than the PDZ
domains to form a tripartite scaffolding protein complex, which binds to the NR2B subunit of
NMDA (N-methyl-D-aspartate) receptors.
Figure 3 | Kinesin superfamily proteins (KIFs) and cargoes for axonal and dendritic transport. a | A typical neuron,
extending several dendrites (left) and a single thin axon (right) from the cell body. In the axon, microtubules are unipolar, with
the plus ends pointing towards the synaptic terminal. Microtubules form special bundles at the initial segment, which might
serve as the cue for axonal transport. Tubulovesicular organelles are transported anterogradely along microtubules by
KIFs. In the growth cone of an axon collateral, KIF2A controls microtubule dynamics and the extension of collaterals.
Rough endoplasmic reticula are abundant in most parts of the cell body, except for the axon hillock. Dendrites contain some
rough endoplasmic reticlula. Microtubules have mixed polarity in proximal dendrites, but are unipolar in distal dendrites, with
the plus end pointing away from the cell body. Membranous organelles and RNA-containing granules are transported along
microtubules by KIFs. b | KIF5 transports vesicles containing APP (amyloid precursor protien) and APOER2 (apolipoprotein E
receptor 2) by interacting with KLC (kinesin light chain)46,47,51,96,97. Mitochondria are transported by KIF5 and KIF1Bα27,45.
KIF3 transports vesicles associated with fodrin57. KIF1A and KIF1Bβboth transport synaptic vesicle precursors26,31,32. JIPs,
scaffolding proteins of the c-Jun amino (N)-terminal kinase (JNK) signalling pathway; KAP3, kinesin superfamily-associated
protein 3. c | In dendrites, KIF5 transports vesicles containing AMPA (α-amino-3-hydroxy-5-methyl-4-isoxazole propionic
acid) receptors through an interaction between KIF5 and GRIP1 (glutamate receptor-interacting protein 1)68. RNA-containing
granules are also transported by interacting directly with KIF5 (REF. 77). KIF17 transports vesicles containing NMDA
(N-methyl-D-aspartate) receptors by interacting through the LIN complex, a tripartite protein complex containing mammalian
homologues of the Caenhorhabditis elegans presynaptic density zone (PDZ) proteins LIN-2, LIN-7 and LIN-1065.
Different general proposed mechanisms for attachment of kinesin motors to 'cargos'. Comparable mechanisms have also been proposed for dynein motors, but, for simplicity, only kinesins are shown. Motor proteins might link directly to transmembrane proteins, to scaffold proteins that link to transmembrane proteins, to proteinaceous raft complexes that bind to other protein cargos or possibly directly to other cytoskeletal filaments. How the dynactin complex, which in some cases might link dynein to spectrin networks on vesicles, fits into these mechanisms is unclear. See main text for additional details.
Fig. 1. Dynein architecture and heavy chain organization. (a) Model of a generic two-headed dynein particle indicating the general location of various structural and functional domains described in the text. (b) Map of the dynein heavy chain identifying the segments of these large proteins involved in binding the IC/LC complex, ATP and microtubules.