Regulation of Endosomal Motility and Degradation by Amyotrophic Lateral Sclerosis 2/alsin

Overview

Journal Mol Brain

Publisher Biomed Central

Specialties Molecular Biology
Neurology

Date 2009 Jul 28

PMID 19630956

Citations 33

Authors

Chen Lai

Chengsong Xie

Hoon Shim

Jayanth Chandran

Brian W Howell

Huaibin Cai

Affiliations

Soon will be listed here.

Abstract

Dysfunction of alsin, particularly its putative Rab5 guanine-nucleotide-exchange factor activity, has been linked to one form of juvenile onset recessive familial amyotrophic lateral sclerosis (ALS2). Multiple lines of alsin knockout (ALS2(-/-)) mice have been generated to model this disease. However, it remains elusive whether the Rab5-dependent endocytosis is altered in ALS2(-/-) neurons. To directly examine the Rab5-mediated endosomal trafficking in ALS2(-/-) neurons, we introduced green fluorescent protein (GFP)-tagged Rab5 into cultured hippocampal neurons to monitor the morphology and motility of Rab5-associated early endosomes. Here we report that Rab5-mediated endocytosis was severely altered in ALS2(-/-) neurons. Excessive accumulation of Rab5-positive vesicles was observed in ALS2(-/-) neurons, which correlated with a significant reduction in endosomal motility and augmentation in endosomal conversion to lysosomes. Consequently, a significant increase in endosome/lysosome-dependent degradation of internalized glutamate receptors was observed in ALS2(-/-) neurons. These phenotypes closely resembled the endosomal trafficking abnormalities induced by a constitutively active form of Rab5 in wild-type neurons. Therefore, our findings reveal a negatively regulatory mechanism of alsin in Rab5-mediated endosomal trafficking, suggesting that enhanced endosomal degradation in ALS2(-/-) neurons may underlie the pathogenesis of motor neuron degeneration in ALS2 and related motor neuron diseases.

Citing Articles

Endosomal traffic disorders: a driving force behind neurodegenerative diseases.

Dong J, Tong W, Liu M, Liu M, Liu J, Jin X Transl Neurodegener. 2024; 13(1):66.

PMID: 39716330 PMC: 11667944. DOI: 10.1186/s40035-024-00460-7.

lncRNA Sequencing Reveals Neurodegeneration-Associated FUS Mutations Alter Transcriptional Landscape of iPS Cells That Persists in Motor Neurons.

Provasek V, Kodavati M, Guo W, Wang H, Boldogh I, Van Den Bosch L Cells. 2023; 12(20).

PMID: 37887305 PMC: 10604943. DOI: 10.3390/cells12202461.

The endolysosomal pathway and ALS/FTD.

Todd T, Shao W, Zhang Y, Petrucelli L Trends Neurosci. 2023; 46(12):1025-1041.

PMID: 37827960 PMC: 10841821. DOI: 10.1016/j.tins.2023.09.004.

Obatoclax Rescues FUS-ALS Phenotypes in iPSC-Derived Neurons by Inducing Autophagy.

Castillo Bautista C, Eismann K, Gentzel M, Pelucchi S, Mertens J, Walters H Cells. 2023; 12(18).

PMID: 37759469 PMC: 10527391. DOI: 10.3390/cells12182247.

lncRNA Sequencing Reveals Neurodegeneration-associated FUS Mutations Alter Transcriptional Landscape of iPS Cells That Persists In Motor Neurons.

Provasek V, Kodavati M, Guo W, Wang H, Boldogh I, Van Den Bosch L Res Sq. 2023; .

PMID: 37461717 PMC: 10350127. DOI: 10.21203/rs.3.rs-3112246/v1.

References

Hadano S, Otomo A, Suzuki-Utsunomiya K, Kunita R, Yanagisawa Y, Showguchi-Miyata J . ALS2CL, the novel protein highly homologous to the carboxy-terminal half of ALS2, binds to Rab5 and modulates endosome dynamics. FEBS Lett. 2004; 575(1-3):64-70. DOI: 10.1016/j.febslet.2004.07.092. View

Otomo A, Hadano S, Okada T, Mizumura H, Kunita R, Nishijima H . ALS2, a novel guanine nucleotide exchange factor for the small GTPase Rab5, is implicated in endosomal dynamics. Hum Mol Genet. 2003; 12(14):1671-87. DOI: 10.1093/hmg/ddg184. View

Ben Hamida M, Hentati F, Ben Hamida C . Hereditary motor system diseases (chronic juvenile amyotrophic lateral sclerosis). Conditions combining a bilateral pyramidal syndrome with limb and bulbar amyotrophy. Brain. 1990; 113 ( Pt 2):347-63. DOI: 10.1093/brain/113.2.347. View

Suzuki-Utsunomiya K, Hadano S, Otomo A, Kunita R, Mizumura H, Osuga H . ALS2CL, a novel ALS2-interactor, modulates ALS2-mediated endosome dynamics. Biochem Biophys Res Commun. 2007; 354(2):491-7. DOI: 10.1016/j.bbrc.2006.12.229. View

Driskell O, Mironov A, Allan V, Woodman P . Dynein is required for receptor sorting and the morphogenesis of early endosomes. Nat Cell Biol. 2006; 9(1):113-20. DOI: 10.1038/ncb1525. View

Cleveland D, Rothstein J . From Charcot to Lou Gehrig: deciphering selective motor neuron death in ALS. Nat Rev Neurosci. 2001; 2(11):806-19. DOI: 10.1038/35097565. View

Cooper J, Salehi A, Delcroix J, Howe C, Belichenko P, Kilbridge J . Failed retrograde transport of NGF in a mouse model of Down's syndrome: reversal of cholinergic neurodegenerative phenotypes following NGF infusion. Proc Natl Acad Sci U S A. 2001; 98(18):10439-44. PMC: 56979. DOI: 10.1073/pnas.181219298. View

Hadano S, Benn S, Kakuta S, Otomo A, Sudo K, Kunita R . Mice deficient in the Rab5 guanine nucleotide exchange factor ALS2/alsin exhibit age-dependent neurological deficits and altered endosome trafficking. Hum Mol Genet. 2005; 15(2):233-50. DOI: 10.1093/hmg/ddi440. View

Nixon R . Endosome function and dysfunction in Alzheimer's disease and other neurodegenerative diseases. Neurobiol Aging. 2005; 26(3):373-82. DOI: 10.1016/j.neurobiolaging.2004.09.018. View

10.

Topp J, Gray N, Gerard R, Horazdovsky B . Alsin is a Rab5 and Rac1 guanine nucleotide exchange factor. J Biol Chem. 2004; 279(23):24612-23. DOI: 10.1074/jbc.M313504200. View

11.

Cai H, Lin X, Xie C, Laird F, Lai C, Wen H . Loss of ALS2 function is insufficient to trigger motor neuron degeneration in knock-out mice but predisposes neurons to oxidative stress. J Neurosci. 2005; 25(33):7567-74. PMC: 2364727. DOI: 10.1523/JNEUROSCI.1645-05.2005. View

12.

de Hoop M, Huber L, Stenmark H, Williamson E, Zerial M, Parton R . The involvement of the small GTP-binding protein Rab5a in neuronal endocytosis. Neuron. 1994; 13(1):11-22. DOI: 10.1016/0896-6273(94)90456-1. View

13.

Gros-Louis F, Meijer I, Hand C, Dube M, MacGregor D, Devon R . An ALS2 gene mutation causes hereditary spastic paraplegia in a Pakistani kindred. Ann Neurol. 2003; 53(1):144-5. DOI: 10.1002/ana.10422. View

14.

Devon R, Orban P, Gerrow K, Barbieri M, Schwab C, Cao L . Als2-deficient mice exhibit disturbances in endosome trafficking associated with motor behavioral abnormalities. Proc Natl Acad Sci U S A. 2006; 103(25):9595-600. PMC: 1480452. DOI: 10.1073/pnas.0510197103. View

15.

Howe C, Granger B, Hull M, Green S, Gabel C, Helenius A . Derived protein sequence, oligosaccharides, and membrane insertion of the 120-kDa lysosomal membrane glycoprotein (lgp120): identification of a highly conserved family of lysosomal membrane glycoproteins. Proc Natl Acad Sci U S A. 1988; 85(20):7577-81. PMC: 282235. DOI: 10.1073/pnas.85.20.7577. View

16.

Bruijn L, Miller T, Cleveland D . Unraveling the mechanisms involved in motor neuron degeneration in ALS. Annu Rev Neurosci. 2004; 27:723-49. DOI: 10.1146/annurev.neuro.27.070203.144244. View

17.

Silver M, Stryker M . A method for measuring colocalization of presynaptic markers with anatomically labeled axons using double label immunofluorescence and confocal microscopy. J Neurosci Methods. 2000; 94(2):205-15. DOI: 10.1016/s0165-0270(99)00145-4. View

18.

Lai C, Xie C, McCormack S, Chiang H, Michalak M, Lin X . Amyotrophic lateral sclerosis 2-deficiency leads to neuronal degeneration in amyotrophic lateral sclerosis through altered AMPA receptor trafficking. J Neurosci. 2006; 26(45):11798-806. PMC: 2556290. DOI: 10.1523/JNEUROSCI.2084-06.2006. View

19.

Jacquier A, Buhler E, Schafer M, Bohl D, Blanchard S, Beclin C . Alsin/Rac1 signaling controls survival and growth of spinal motoneurons. Ann Neurol. 2006; 60(1):105-17. DOI: 10.1002/ana.20886. View

20.

Satoh D, Sato D, Tsuyama T, Saito M, Ohkura H, Rolls M . Spatial control of branching within dendritic arbors by dynein-dependent transport of Rab5-endosomes. Nat Cell Biol. 2008; 10(10):1164-71. DOI: 10.1038/ncb1776. View