Quantitative Transportomics Identifies Kif5a As a Major Regulator of Neurodegeneration

Overview

Journal Elife

Specialty Biology

Date 2022 Mar 8

PMID 35259089

Authors

Sahil H Shah

Lucio M Schiapparelli

Yuanhui Ma

Satoshi Yokota

Melissa Atkins

Xin Xia

Evan G Cameron

Thanh Huang

Sarah Saturday

Catalina B Sun

Cara Knasel

Seth Blackshaw

John R Yates

Hollis T Cline

Jeffrey L Goldberg

Affiliations

Soon will be listed here.

Abstract

Many neurons in the adult central nervous system, including retinal ganglion cells (RGCs), degenerate and die after injury. Early axon protein and organelle trafficking failure is a key component in many neurodegenerative disorders yet changes to axoplasmic transport in disease models have not been quantified. We analyzed early changes in the protein 'transportome' from RGC somas to their axons after optic nerve injury and identified transport failure of an anterograde motor protein Kif5a early in RGC degeneration. We demonstrated that manipulating Kif5a expression affects anterograde mitochondrial trafficking in RGCs and characterized axon transport in Kif5a knockout mice to identify proteins whose axon localization was Kif5a-dependent. Finally, we found that knockout of Kif5a in RGCs resulted in progressive RGC degeneration in the absence of injury. Together with expression data localizing Kif5a to human RGCs, these data identify Kif5a transport failure as a cause of RGC neurodegeneration and point to a mechanism for future therapeutics.

Citing Articles

Optineurin-facilitated axonal mitochondria delivery promotes neuroprotection and axon regeneration.

Liu D, Webber H, Bian F, Xu Y, Prakash M, Feng X Nat Commun. 2025; 16(1):1789.

PMID: 39979261 PMC: 11842812. DOI: 10.1038/s41467-025-57135-8.

The role of RGC degeneration in the pathogenesis of glaucoma.

Si Z, Fan Y, Wang M, Zhao J, Zhang Y, Liu D Int J Biol Sci. 2025; 21(1):211-232.

PMID: 39744428 PMC: 11667808. DOI: 10.7150/ijbs.103222.

Mechanism and regulation of kinesin motors.

Yildiz A Nat Rev Mol Cell Biol. 2024; 26(2):86-103.

PMID: 39394463 DOI: 10.1038/s41580-024-00780-6.

KIF5A regulates axonal repair and time-dependent axonal transport of SFPQ granules and mitochondria in human motor neurons.

Guerra San Juan I, Brunner J, Eggan K, Toonen R, Verhage M bioRxiv. 2024; .

PMID: 39314491 PMC: 11418931. DOI: 10.1101/2024.09.06.611684.

Optineurin-facilitated axonal mitochondria delivery promotes neuroprotection and axon regeneration.

Liu D, Webber H, Bian F, Xu Y, Prakash M, Feng X bioRxiv. 2024; .

PMID: 38617277 PMC: 11014509. DOI: 10.1101/2024.04.02.587832.

References

Tessa A, Silvestri G, de Leva M, Modoni A, Denora P, Masciullo M . A novel KIF5A/SPG10 mutation in spastic paraplegia associated with axonal neuropathy. J Neurol. 2008; 255(7):1090-2. DOI: 10.1007/s00415-008-0840-8. View

Liddelow S, Guttenplan K, Clarke L, Bennett F, Bohlen C, Schirmer L . Neurotoxic reactive astrocytes are induced by activated microglia. Nature. 2017; 541(7638):481-487. PMC: 5404890. DOI: 10.1038/nature21029. View

Moore D, Blackmore M, Hu Y, Kaestner K, Bixby J, Lemmon V . KLF family members regulate intrinsic axon regeneration ability. Science. 2009; 326(5950):298-301. PMC: 2882032. DOI: 10.1126/science.1175737. View

Kim H, Kim N, Wang Y, Scarborough E, Moore J, Diaz Z . Mutations in prion-like domains in hnRNPA2B1 and hnRNPA1 cause multisystem proteinopathy and ALS. Nature. 2013; 495(7442):467-73. PMC: 3756911. DOI: 10.1038/nature11922. View

Zheng G, Terry J, Belgrader P, Ryvkin P, Bent Z, Wilson R . Massively parallel digital transcriptional profiling of single cells. Nat Commun. 2017; 8:14049. PMC: 5241818. DOI: 10.1038/ncomms14049. View

Hoang T, Wang J, Boyd P, Wang F, Santiago C, Jiang L . Gene regulatory networks controlling vertebrate retinal regeneration. Science. 2020; 370(6519). PMC: 7899183. DOI: 10.1126/science.abb8598. View

Gumy L, Katrukha E, Grigoriev I, Jaarsma D, Kapitein L, Akhmanova A . MAP2 Defines a Pre-axonal Filtering Zone to Regulate KIF1- versus KIF5-Dependent Cargo Transport in Sensory Neurons. Neuron. 2017; 94(2):347-362.e7. DOI: 10.1016/j.neuron.2017.03.046. View

McKerracher L, Vidal-Sanz M, Essagian C, Aguayo A . Selective impairment of slow axonal transport after optic nerve injury in adult rats. J Neurosci. 1990; 10(8):2834-41. PMC: 6570264. View

Speers A, Cravatt B . Activity-Based Protein Profiling (ABPP) and Click Chemistry (CC)-ABPP by MudPIT Mass Spectrometry. Curr Protoc Chem Biol. 2011; 1:29-41. PMC: 3119539. DOI: 10.1002/9780470559277.ch090138. View

10.

Yasuda M, Tanaka Y, Omodaka K, Nishiguchi K, Nakamura O, Tsuda S . Transcriptome profiling of the rat retina after optic nerve transection. Sci Rep. 2016; 6:28736. PMC: 4926057. DOI: 10.1038/srep28736. View

11.

Park K, Liu K, Hu Y, Kanter J, He Z . PTEN/mTOR and axon regeneration. Exp Neurol. 2010; 223(1):45-50. DOI: 10.1016/j.expneurol.2009.12.032. View

12.

Hendricks A, Perlson E, Ross J, Schroeder 3rd H, Tokito M, Holzbaur E . Motor coordination via a tug-of-war mechanism drives bidirectional vesicle transport. Curr Biol. 2010; 20(8):697-702. PMC: 2908734. DOI: 10.1016/j.cub.2010.02.058. View

13.

Chevalier-Larsen E, Holzbaur E . Axonal transport and neurodegenerative disease. Biochim Biophys Acta. 2006; 1762(11-12):1094-108. DOI: 10.1016/j.bbadis.2006.04.002. View

14.

MacAskill A, Rinholm J, Twelvetrees A, Arancibia-Carcamo I, Muir J, Fransson A . Miro1 is a calcium sensor for glutamate receptor-dependent localization of mitochondria at synapses. Neuron. 2009; 61(4):541-55. PMC: 2670979. DOI: 10.1016/j.neuron.2009.01.030. View

15.

Schiapparelli L, Shah S, Ma Y, McClatchy D, Sharma P, Li J . The Retinal Ganglion Cell Transportome Identifies Proteins Transported to Axons and Presynaptic Compartments in the Visual System In Vivo. Cell Rep. 2019; 28(7):1935-1947.e5. PMC: 6707540. DOI: 10.1016/j.celrep.2019.07.037. View

16.

Deshaies J, Shkreta L, Moszczynski A, Sidibe H, Semmler S, Fouillen A . TDP-43 regulates the alternative splicing of hnRNP A1 to yield an aggregation-prone variant in amyotrophic lateral sclerosis. Brain. 2018; 141(5):1320-1333. PMC: 5917749. DOI: 10.1093/brain/awy062. View

17.

Loschi M, Leishman C, Berardone N, Boccaccio G . Dynein and kinesin regulate stress-granule and P-body dynamics. J Cell Sci. 2009; 122(Pt 21):3973-82. PMC: 2773196. DOI: 10.1242/jcs.051383. View

18.

Ishida M, Ohbayashi N, Fukuda M . Rab1A regulates anterograde melanosome transport by recruiting kinesin-1 to melanosomes through interaction with SKIP. Sci Rep. 2015; 5:8238. PMC: 4316160. DOI: 10.1038/srep08238. View

19.

Quigley H, Anderson D . Distribution of axonal transport blockade by acute intraocular pressure elevation in the primate optic nerve head. Invest Ophthalmol Vis Sci. 1977; 16(7):640-4. View

20.

Zhao C, Takita J, Tanaka Y, Setou M, Nakagawa T, Takeda S . Charcot-Marie-Tooth disease type 2A caused by mutation in a microtubule motor KIF1Bbeta. Cell. 2001; 105(5):587-97. DOI: 10.1016/s0092-8674(01)00363-4. View