Research:
Our laboratory seeks to explain how axons are guided to the correct sites during development and to describe the extent to which axonal connectivity is fixed or malleable in the adult. Our previous work has identified the myelin-derived inhibitory protein, Nogo-A, and an axonal Nogo-66 Receptor (NgR1) as inhibitors of axonal regeneration after adult brain or spinal injury. The natural function of this system is to limit adult brain plasticity and to reduce the risk of psychiatric disease. We are exploring the physiological role of NgR in brain plasticity by imaging intact neurons in living animals with a two-photon microscope through windows in the skull. We are also developing blockers of this system using structural biology, mutagenesis and high-throughput screening methods. Such antagonists are now shown to exhibit dramatic regenerative efficacy in the treatment of CNS injury, including spinal cord trauma and stroke.
We have initiated studies in the neuronal degeneration in Alzheimer’s Disease (AD) and Frontotemporal Dementia (FTD). In both of these diseases, specific extracellular peptides are implicated in the disease process, but the neuronal receptor which mediates the peptide effect is not known. Using expression cloning methods, we have identified high affinity binding sites for the Aß oligomers of AD and the progranulin/granulin peptides of FTD. We are characterizing the significance and receptor-type action of these high affinity binding sites for Aß and Progranulin.
Recent references:
Hu F, Strittmatter SM. The N-terminal domain of Nogo-A inhibits cell adhesion and axonal outgrowth by an integrin-specific mechanism. J Neurosci. 30:1262-1269 (2008).
Schmidt E, Shim SO, Strittmatter SM. Release Of MICAL Auto-inhibition By Semaphorin-Plexin Signaling Promotes Interaction With CRMP. J Neurosci. 28:2287-2297 (2008).
Budel S, Padukkavidana T, Liu BP, Feng Z, Hu F, Johnson S, Lauren J, Park JH, McGee AW, Liao J, Stillman A, Kim JE, Yang BZ, Sodi S, Gelernter J, Zhao H, Hisama F, Arnsten AF, Strittmatter SM. Genetic variants of Nogo-66 receptor with possible association to schizophrenia block myelin inhibition of axon growth. J Neurosci. 28:13161-13172 (2008).
Wang X, Budel S, Baughman K, Gould G, Song KH, Strittmatter SM. Ibuprofen Enhances Recovery from Spinal Cord Injury by Limiting Tissue Loss and Stimulating Axonal Growth. J Neurotrauma. 2009 Jan 6. [Epub ahead of print]
Linhoff MW, Laurén J, Cassidy RM, Dobie FA, Takahashi H, Nygaard HB, Airaksinen MS, Strittmatter SM, Craig AM. An Unbiased Expression Screen for Synaptogenic Proteins Identifies the LRRTM Protein Family as Synaptic Organizers. Neuron 61:734-749 (2009).
Laurén J, Gimbel DA, Nygaard HB, Gilbert JW, Strittmatter SM. Cellular Prion Protein Mediates Impairment of Synaptic Plasticity by Amyloid-ß Oligomers. Nature 457:1128-1132 (2009).
Key References
Goshima Y, Nakamura F, Strittmatter P, Strittmatter SM. Collapsin-induced growth cone collapse mediated by an intracellular protein related to unc-33. Nature, 376: 509-514 (1995).
Takahashi T, Fournier A, Nakamura F, Wang, LH, Murakami Y, Kalb RG, Fujisawa H, Strittmatter SM. Plexin-neuropilin1 complexes form functional semaphorin-3A receptors. Cell 99: 59-69, (1999).
Grandpre T, Nakamura F, Vartanian T, Strittmatter SM. Identification of the Nogo inhibitor of axon regeneration as a Reticulon protein. Nature, 403: 439-444 (2000).
Fournier A, GrandPre T, Strittmatter SM. Identification of a neuronal receptor mediating Nogo-66 inhibition of axonal regeneration. Nature 409:341-346 (2001).
GrandPre T, Li S, Strittmatter SM. Nogo-66 Receptor Antagonist Peptide Promotes Axonal Regeneration, Nature 417: 547-551 (2002).
Liu B, Fournier A, GrandPre T Strittmatter SM. Myelin-Associated Glycoprotein As A Functional Ligand For The Nogo-66 Receptor. Science, 297:1190-1193 (2002).
Kim JE, Li S, GrandPré T, Qiu D, Strittmatter SM. Axon Regeneration in Young Adult Mice Lacking Nogo-A/B. Neuron, 38, 187-199 (2003).
Kim JE, Liu BP. Park JH, Strittmatter SM. Nogo-66 Receptor Prevents Raphespinal and Rubrospinal Axon Regeneration and Limits Functional Recovery from Spinal Cord Injury. Neuron 44:439-451 (2004).
McGee W, Yang Y, Fischer QW, Daw N, Strittmatter SM. Experience-Driven Plasticity Of Visual Cortex Restricted By Myelin And Nogo Receptor. Science 309: 2222-2226 (2005).
Laurén J, Gimbel DA, Nygaard HB, Gilbert JW, Strittmatter SM. Cellular Prion Protein Mediates Impairment of Synaptic Plasticity by Amyloid-ß Oligomers. Nature 457:1128-1132 (2009).
