How REEP1 mutations cause HSP clarified

Involved with both mitochondria and ER


Mutations in the REEP1 gene are known to cause SPG31 type HSP but there have been conflicting findings to date with some studies associating mutations with impairment to the endoplasmic reticulum (ER) while other studies found impairment to mitochondria.


This in-depth study showed that REEP1 is found in both locations; that healthy REEP1 facilitates interactions between the ER and mitochondria; and that disease associated mutations impair these interactions.


The study also showed that the test (assay) used to measure ER–mitochondria interaction defects can be used to identify potential drug treatments for multiple neurodegenerative diseases that exhibit these defects.




Mutations in receptor expression enhancing protein 1 (REEP1) are associated with hereditary spastic paraplegias (HSPs). Although axonal degeneration is thought to be a predominant feature in HSP, the role of REEP1 mutations in degeneration is largely unknown. Previous studies have implicated a role for REEP1 in the endoplasmic reticulum (ER), whereas others localized REEP1 with mitochondria. We sought to resolve the cellular localization of REEP1 and to further elucidate the pathobiology underlying REEP1 mutations in patients.



A combination of cellular imaging and biochemical approaches was used to refine the cellular localization of REEP1. Next, REEP1 mutations associated with HSP were functionally tested in neuritic growth and degeneration assays using mouse cortical culture. Finally, a novel assay was developed and used with wild type and mutant REEP1s to measure the interactions between the ER and mitochondria.



We found that REEP1 is present at the ER-mitochondria interface, and it contains sub-domains for mitochondrial as well as ER localization. Knockdown of REEP1 and the expression of pathological REEP1 mutations resulted in neuritic growth defects and degeneration. Finally, using our novel split-RLuc8 assay, we show REEP1 facilitates ER-mitochondria interactions, a function diminished by disease-associated mutations.



Our data potentially reconcile the current conflicting reports regarding REEP1 being either an ER or a mitochondrial protein. Furthermore, our results connect, for the first time, the disrupted ER-mitochondria interactions to a failure in maintaining health of long axons in HSPs. Finally, the split-RLuc8 assay offers a new tool to identify potential drugs for multiple neurodegenerative diseases with ER-mitochondria interaction defects. This article is protected by copyright. All rights reserved.


SOURCE: Ann Neurol. 2015 Jul 22. doi: 10.1002/ana.24488. [Epub ahead of print] © 2015 American Neurological Association. PMID: 26201691 [PubMed – as supplied by publisher]


Hereditary Spastic Paraplegia-Linked REEP1 Modulates ER-Mitochondria Contacts.


Lim Y1, Cho IT1, Schoel LJ1, Cho G1, Golden JA1.

  • 1Department of Pathology, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, 02115.


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