Axonal transport and neurodegenerative disease: vesicle-motor complex formation and their regulation

Figures & data

Figure 1 Conventional kinesin (kinesin-1) and cytoplasmic dynein motor complex on a MT for axonal transport.

Notes: Kinesin-1 through the KHC head motor domains binds MTs. Vesicles associate with kinesin-1 via associations with the KLC or via adaptor scaffolding proteins. Cargo complexes attached to kinesin-1 are transported anterogradely (toward + end of MTs; arrow). Cytoplasmic dynein associates with dynactin for retrograde movement. Dynactin consists of multiple proteins, but only p150Glued and p50 are shown for simplicity. Dynein interacts with dynactin via associations between p150Glued and DIC subunits. Dynein binds MTs via the tip of the stalk of DHC, while dynactin also associates with MTs via the N-terminal globular domain of p150Glued. Dynein–dynactin motor complex transports cargoes retrogradely (toward – end of the MTs; arrow).
Abbreviations: KHC, kinesin heavy chain; MTs, microtubules; KLC, kinesin light chain; DHC, dynein heavy chain; DIC, dynein intermediate chain; DLC, dynein light chain.

Table 1 Vesicle-motor complexes associated with neurodegenerative diseases

Cargo/vesicle complex	Motor protein involved	Complex components	Disease	References
APP	KHC, KLC, dynein	PS1, GAP-43, BACE, TrKA, synapsin, JIP1, JIP3	Alzheimer’s disease	^Citation36, ^Citation98, ^Citation100, ^Citation101, ^Citation102, ^Citation119
HTT	KIF5, KLC, dynein	HAP1, HAP40, GAPDH Rab11, BDNF	Huntington’s disease	^Citation35, ^Citation124, ^Citation127, ^Citation128, ^Citation129, ^Citation190, ^Citation218, ^Citation219
Mitochondria	KIF5, KIF1B-alpha,dynein	Milton–Miro complex, JIP1, RanB2, pink-parkin,Mfn2, syntabulin	Parkinson’s disease, CMT2A	^Citation138, ^Citation142, ^Citation145^–^Citation148,Citation157, ^Citation208, ^Citation209
mRNA–protein complex	KIF5, dynein	FMRP, La mRNA	Fragile X syndrome	^Citation165, ^Citation172, ^Citation175

Abbreviations: APP, amyloid precursor protein; HTT, huntingtin; KHC, kinesin heavy chain; KLC, kinesin light chain; PS1, presenilin 1; GAP43, growth-associated protein 43; BACE, beta-site amyloid precursor protein cleaving enzyme; TrKA, tyrosine kinase receptor type A; JIP1, c-Jun-amino-terminal kinase-interacting protein 1; JIP3, c-Jun-amino-terminal kinase-interacting protein 3; HAP1, huntingtin-associated protein 1; HAP40, huntingtin-associated protein 40; GAPDH, glyceraldehyde 3-phosphate dehydrogenase; BDNF, brain-derived neurotrophic factor; Mfn, mitofusin; CMT, Charcot–Marie–Tooth; FMRP, Fragile X mental retardation protein.

Figure 2 Models of APP-cargo complexes and their regulation during transport.

Notes: (A) APP can associate with kinesin-1 in two ways. APP associates with kinesin-1 via interactions with JIP1. This interaction may require APP to be phosphorylated at T668. Alternatively, the C-terminus of APP can associate with kinesin-1 via KLC through its TPR domains. (B) JNK phosphorylation of JIP1 at S421 regulates APP association with kinesin-1 and dynein. Phosphorylation of JIP1 is thought to promote anterograde transport, while dephosphorylation promotes retrograde transport. Arrows indicate direction of motility. (C) APP is in a vesicular compartment that contains BACE, PS1, GAP43, synapsin, and TrkA. PS1 is the catalytic component of gamma (γ) secretase that is known to cleave (scissor) APP and may serve to release APP vesicles from motors. (D) PS1 contains two putative glycogen synthase kinase 3-beta (GSK-3β) phosphorylation sites in its loop region. Phosphorylated PS1 may serve as a scaffold for GSK-3β to associate with PS1 similar to the β-catenin-PS interaction, thus enabling GSK-3β to phosphorylate kinesin, which may release the vesicle from kinesin-1 or regulate motility of APP vesicles. It remains unclear whether these events are specific to APP vesicles or are general to all vesicles.
Abbreviations: APP, amyloidal precursor protein; T668, threonine 668; S421, serine 421; JIP1, Jun N kinase interacting protein 1; KLC, kinesin light chain; TPR, tetratricopeptide repeat; JNK, Jun N kinase; BACE, beta-site amyloid precursor protein cleaving enzyme; PS1, presenilin; GAP43, growth-associated protein 43; TrkA, tyrosine kinase receptor type A.

Figure 3 Models of HTT-cargo complexes and their regulation during transport. Notes: (A) HTT may attach to BDNF or Rab protein containing vesicles and associate with kinesin-1 and dynein via interactions with HAP1 and HAP40. (B) Akt can phosphorylate HTT at S421 causing it to stabilize kinesin-1 and increase anterograde transport of BDNF vesicles. Dephosphorylation of HTT at S421 and possibly phosphorylation of HAP1 by PKA may destabilize kinesin, enabling HAP1 to associate with p150Glued and increase retrograde transport. (C) Pathogenic HTT (HTT polyQ) activates JNK3, a neuronal specific kinase, to phosphorylate KHC and release kinesin-1 from MTs.

Abbreviations: HTT, huntingtin; polyQ, polyglutamine; BDNF, brain-derived neurotrophic factor; HAP1, huntingtin-associated protein 1; HAP40, huntingtin-associated protein 40; S421, serine 421; PKA, protein kinase A; JNK3, Jun N kinase 3; KHC, kinesin heavy chain; MTs, microtubules.

Figure 4 Proposed models of mitochondrial cargo complexes and their regulation during transport.

Notes: (A) Rho-GTPase Miro and Milton form a complex in which Milton serves as an adaptor to link the Miro/mitochondria complex to KHC. (B) Mfn2 associates with the Miro/Milton complex. PINK1 phosphorylates Miro at S156 to release damaged mitochondria from kinesin-1. (C) SNPH acts as an anchor to halt transport of mitochondria in the presence of Ca²⁺. (D) Ca²⁺ binding to the EF-hand helix–loop–helix structural domain of Miro induces KHC to bind Miro instead of MT or Ca2+ binding to Miro detaches the Milton/Miro complex from KHC, resulting in mitochondria to becoming stationary.
Abbreviations: GTP, guanosine triphosphate; Mfn, mitofusin; KHC, kinesin heavy chain; PINK, PTEN induced kinase 1; SNPH, syntaphilin; MT, microtubules.

Xia CH, Roberts EA, Her LS, et al Abnormal neurofilament transport caused by targeted disruption of neuronal kinesin heavy chain KIF5A. J Cell Biol. 2003;161(1):55–66.12682084

 PubMed Web of Science ®Google Scholar

Müller MJ, Klumpp S, Lipowsky R. Tug-of-war as a cooperative mechanism for bidirectional cargo transport by molecular motors. Proc Natl Acad Sci U S A. 2008;105(12):4609–4614.18347340

 PubMed Web of Science ®Google Scholar

Hendricks AG, Perlson E, Ross JL, Schroeder HW 3rd, Tokito M, Holzbaur EL. Motor coordination via a tug-of-war mechanism drives bidirectional vesicle transport. Curr Biol. 2010;20(8):697–702.20399099

 PubMed Web of Science ®Google Scholar

Kural C, Kim H, Syed S, Goshima G, Gelfand VI, Selvin PR. Kinesin and dynein move a peroxisome in vivo: a tug-of-war or coordinated movement? Science. 2005;308(5727):1469–1472.15817813

 PubMed Web of Science ®Google Scholar

Barkus RV, Klyachko O, Horiuchi D, Dickson BJ, Saxton WM. Identification of an axonal kinesin-3 motor for fast anterograde vesicle transport that facilitates retrograde transport of neuropeptides. Mol Biol Cell. 2008;19(1):274–283.17989365

 PubMed Web of Science ®Google Scholar

Van den Heuvel C, Blumbergs PC, Finnie JW, et al Upregulation of amyloid precursor protein messenger RNA in response to traumatic brain injury: an ovine head impact model. Exp Neurol. 1999;159(2): 441–450.10506515

 PubMed Web of Science ®Google Scholar

Tanaka Y, Kanai Y, Okada Y, et al Targeted disruption of mouse conventional kinesin heavy chain, kif5B, results in abnormal perinuclear clustering of mitochondria. Cell. 1998;93(7):1147–1158.9657148

 PubMed Web of Science ®Google Scholar

Gunawardena S, Goldstein LS. Disruption of axonal transport and neuronal viability by amyloid precursor protein mutations in Drosophila. Neuron. 2001;32(3):389–401.11709151

 PubMed Web of Science ®Google Scholar

Rodrigues EM, Weissmiller AM, Goldstein LS. Enhanced β-secretase processing alters APP axonal transport and leads to axonal defects. Hum Mol Genet. 2012;21(21):4587–4601.22843498

 PubMed Web of Science ®Google Scholar

Gunawardena S, Yang G, Goldstein LS. Presenilin controls kinesin-1 and dynein function during APP-vesicle transport in vivo. Hum Mol Genet. 2013;22(19):3828–3843.23710041

 PubMed Web of Science ®Google Scholar

Kamal A, Almenar-Queralt A, LeBlanc JF, Roberts EA, Goldstein LS. Kinesin-mediated axonal transport of a membrane compartment containing beta-secretase and presenilin-1 requires APP. Nature. 2001;414(6864):643–648.11740561

 PubMed Web of Science ®Google Scholar

Chen Y, Sheng ZH. (2013, Kinesin-1-syntaphilin coupling mediates activity-dependent regulation of axonal mitochondrial transport. J Cell Biol. 202(2):351–364.23857772

 PubMed Web of Science ®Google Scholar

Pathak GK, Love JM, Chetta J, Shah SB. A comparative quantitative assessment of axonal and dendritic mRNA transport in maturing hippocampal neurons. PLoS One. 2013;8(7):e65917.23894274

 PubMed Web of Science ®Google Scholar

Savas JN, Ma B, Deinhardt K, et al A role for huntington disease protein in dendritic RNA granules. J Biol Chem. 2010;285(17): 13142–13153.20185826

 PubMed Web of Science ®Google Scholar

Weaver C, Leidel C, Szpankowski L, Farley NM, Shubeita GT, Goldstein LS. Endogenous GSK-3/shaggy regulates bidirectional axonal transport of the amyloid precursor protein. Traffic. 2013;14(3):295–308.23279138

 PubMed Web of Science ®Google Scholar

Stokin GB, Lillo C, Falzone TL, et al Axonopathy and transport deficits early in the pathogenesis of Alzheimer’s disease. Science. 2005;307(5713):1282–1288.15731448

 PubMed Web of Science ®Google Scholar

Takano H, Gusella JF. The predominantly HEAT-like motif structure of huntingtin and its association and coincident nuclear entry with dorsal, an NF-κB/Rel/dorsal family transcription factor. BMC Neurosci. 2002;3:15.12379151

 PubMed Web of Science ®Google Scholar

Dlugosz M, Trylska J. Secondary structures of native and pathogenic huntingtin N-terminal fragments. J Phys Chem B. 2011;115(40): 11597–11608.21910495

 PubMed Web of Science ®Google Scholar

Gauthier LR, Charrin BC, Borrell-Pagès M, et al Huntingtin controls neurotrophic support and survival of neurons by enhancing BDNF vesicular transport along microtubules. Cell. 2004;118(1):127–138.15242649

 PubMed Web of Science ®Google Scholar

Rintoul GL, Filiano AJ, Brocard JB, Kress GJ, Reynolds IJ. Glutamate decrease mitochondrial size and movement in primary forebrain neurons. J Neurosci. 2003;23(21):7881–7888.12944518

 PubMed Web of Science ®Google Scholar

Dolma K, Iacobucci GJ, Hong Zheng K, et al Presenilin influences glycogen synthase kinase-3β (GSK-3β) for kinesin-1 and dynein function during axonal transport. Hum Mol Genet. Epub October 18, 2013.

 Google Scholar

Richards P, Didszun C, Campesan S, et al Dendritic spine loss and neurodegeneration is rescued by Rab11 in models of Huntington’s disease. Cell Death Differ. 2011;18(2):191–200.21217767

 PubMed Web of Science ®Google Scholar

Morfini GA, You YM, Pollema SL, et al Pathogenic huntingtin inhibits fast axonal transport by activating JNK3 and phosphorylating kinesin. Nat Neurosci. 2009;12(7):864–871.19525941

 PubMed Web of Science ®Google Scholar

Hollenbeck PJ, Saxton WM. The axonal transport of mitochondria. J Cell Sci. 2005;118(Pt 23):5411–5419.16306220

 PubMed Web of Science ®Google Scholar