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4136 The Journal of Clinical Investigation http://www.jci.org Volume 123 Number 10 October 2013 reveals REEP1-dependent ER shaping. J Clin Invest. 2013;123(10):4273–4282. 12. Friedman JR, Lackner LL, West M, DiBenedetto JR, Nunnari J, Voeltz GK. ER tubules mark sites of mitochondrial division. Science. 2011;334(6054):358–362. 13. Allen Institute for Brain Science. Allen Mouse Brain Atlas. AIBS Web site. http://mouse.brainmap.org/experiment/show/74821680. Accessed August 26, 2013. 14. Zhao J, Matthies DS, Botzolakis EJ, Macdonald RL, Blakely RD, Herrera P. Hereditary spastic paraplegia-associated mutations in the NIPA1 gene and its Caenorhabditis elegans homolog trigger neural degeneration in vitro and in vivo through a gain-of-function mechanism. J Neurosci. 2008; 28(51):13938–13951. 15. Park SH, Zhu PP, Parker RL, Blackstone C. Hereditary spastic paraplegia proteins REEP1, spastin, and atlastin-1 coordinate microtubule interactions with the tubular ER network. J Clin Invest. 2010;120(4):1097–1110. 16. Montenegro G, et al. Mutations in the ER-shaping protein reticulon 2 cause the axon-degenerative disorder hereditary spastic paraplegia type 12. J Clin Invest. 2012;122(2):538–544. 17. Füger P, et al. Spastic paraplegia mutation N256S in the neuronal microtubule motor KIF5A disrupts axonal transport in a Drosophila HSP model. PloS Genet. 2012;8(11):e1003066. 18. Burke RE. Sir Charles Sherrington’s the integrative action of the nervous system: a centenary appreciation. Brain. 2007;130(pt 4):887–894. 19. Shepherd GM. Corticostriatal connectivity and its role in disease. Nat Rev Neurosci. 2013;14(4):278–291. 20. Webb S, et al. Autosomal dominant hereditary spastic paraparesis with cognitive loss linked to chromosome 2p. Brain. 1998;121(pt 4):601–609. motor phenotypes of HSPs. It also remains unclear whether pure HSPs can be linked to cell-autonomous processes or are non-cell autonomous, and indeed whether there are “protective” features in nonspinal targets of upper motoneurons that result in some sparing of neuronal function. In summary, Beetz and colleagues have generated what promises to be a very useful mouse model of HSP. Future studies of these mice should uncover important features of the pathogenic mechanisms underlying this disease. These mice will also be useful in developing a deeper understanding of ER membrane biology. It is likely that we will “REEP” the benefit of this work for some years to come.