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PMID: 20200447 Published · ppublish English Journal Article Research Support, N.I.H., Intramural Research Support, Non-U.S. Gov't

Hereditary spastic paraplegia proteins REEP1, spastin, and atlastin-1 coordinate microtubule interactions with the tubular ER network.

The Journal of clinical investigation ·Vol. 120 ·No. 4 ·2010-04-00 ·Pages 1097-110

Park SH, Zhu PP, Parker RL, Blackstone C

Abstract

Hereditary spastic paraplegias (HSPs; SPG1-45) are inherited neurological disorders characterized by lower extremity spastic weakness. More than half of HSP cases result from autosomal dominant mutations in atlastin-1 (also known as SPG3A), receptor expression enhancing protein 1 (REEP1; SPG31), or spastin (SPG4). The atlastin-1 GTPase interacts with spastin, a microtubule-severing ATPase, as well as with the DP1/Yop1p and reticulon families of ER-shaping proteins, and SPG3A caused by atlastin-1 mutations has been linked pathogenically to abnormal ER morphology. Here we investigated SPG31 by analyzing the distribution, interactions, and functions of REEP1. We determined that REEP1 is structurally related to the DP1/Yop1p family of ER-shaping proteins and localizes to the ER in cultured rat cerebral cortical neurons, where it colocalizes with spastin and atlastin-1. Upon overexpression in COS7 cells, REEP1 formed protein complexes with atlastin-1 and spastin within the tubular ER, and these interactions required hydrophobic hairpin domains in each of these proteins. REEP proteins were required for ER network formation in vitro, and REEP1 also bound microtubules and promoted ER alignment along the microtubule cytoskeleton in COS7 cells. A SPG31 mutant REEP1 lacking the C-terminal cytoplasmic region did not interact with microtubules and disrupted the ER network. These data indicate that the HSP proteins atlastin-1, spastin, and REEP1 interact within the tubularER membrane in corticospinal neurons to coordinate ER shaping and microtubule dynamics. Thus, defects in tubular ER shaping and network interactions with the microtubule cytoskeleton seem to be the predominant pathogenic mechanism of HSP.

MeSH Terms
Adenosine Triphosphatases/physiology Amino Acid Sequence Animals COS Cells Chlorocebus aethiops Endoplasmic Reticulum/physiology GTP Phosphohydrolases/physiology GTP-Binding Proteins Humans Male Membrane Proteins/physiology Membrane Transport Proteins/physiology Microtubules/physiology Molecular Sequence Data Rats Rats, Sprague-Dawley Spastic Paraplegia, Hereditary/etiology Spastin
Chemicals
Membrane Proteins Membrane Transport Proteins REEP1 protein, human REEP5 protein, human ATL1 protein, human Adenosine Triphosphatases GTP Phosphohydrolases GTP-Binding Proteins Spastin SPAST protein, human
Authors & Affiliations
4 authors, click to expand affiliations / ORCID
Park Seong H
Cellular Neurology Unit, Neurogenetics Branch, National Institute of Neurological Disorders and Stroke (NINDS), NIH, Bethesda, Maryland 20892-3738, USA.
Zhu Peng-Peng
Parker Rell L
Blackstone Craig
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Article Info
Journal
The Journal of clinical investigation
Abbr.
J Clin Invest
ISSN
1558-8238
DOI
10.1172/JCI40979
Published
2010-04-00
Pages
1097-110
Language
English
Region
United States
NLM ID
7802877
PMCID
PMC2846052
Subset
IM
Grants
Howard Hughes Medical Institute · United States
Intramural NIH HHS · United States
External Links
PubMed source DOI: 10.1172/JCI40979 PMC Full Text View journal details
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