[olsen]

Protein Helps Neurons Connect, Possibly Reducing Parkinson's Symptoms

Parkinson's Disease

Blocking a protein expressed in dopamine neurons may be able to keep symptoms of Parkinson's disease at bay and even help improve the condition of patients.

In a paper published in the early online edition of the Proceedings of the National Academy of Sciences, a team led by Ole Isacson, Dr. Med. Sc., director of the Neuroregeneration Laboratory and Neuroregeneration Research Center at McLean Hospital, found that a protein called LINGO-1 is able to affect neural connections involving the brain's dopamine system.

"The hope is that LINGO-1 will be one possible example of a way to help the brain maintain its connections," Isacson said. The idea is to find ways to maintain connections between neurons. When such connections are interrupted, brain diseases can take hold.

While LINGO-1 has only been shown to affect Parkinson's, the science being reported in the paper holds promise for fighting other brain diseases as well, Isacson explained. "The science could provide a way to fight against a number of neurodegenerative diseases, including Parkinson's, Alzheimer's, Amyotrophic Lateral Sclerosis and Huntington's," he said.

Parkinson's is a disease characterized by tremors, rigidity, slowness of movement and poor balance. It is a chronic, progressive disease that results when nerve cells in a part of the brain die or are impaired. These nerve cells produce dopamine, an important chemical messenger that transmits signals from one part of the brain to another, according to the National Parkinson Foundation. These signals allow for coordinated movement. When the dopamine-secreting cells die, the other movement control centers in the brain become unregulated.

Isacson's paper notes that new drugs and other therapeutic interventions are needed to simultaneously preserve dopamine neurons and their functional connections to limit or eliminate the progression of the movement disorder.

Other studies have linked the protein LRRK-2 with Parkinson's. Now, this study indicates LINGO-1 may also be linked to the disease. Isacson's study in mice showed that LINGO-1 appears to regulate neuron growth and the structural integrity of neurons, along with LRRK-2. "We found that LINGO-1 is capable of changing the growth of connections in the dopamine system," Isacson said.

The proteins act as growth factors and can cause the connections to either increase or decrease.

Basically, the study found that blocking the function of LINGO-1 works to inhibit the degeneration of dopamine neurons. Isacson said this could be done in a number of ways, including giving antibodies or antagonists that bind to the LINGO-1 protein to block its inhibitory action. "We have started to understand how to maintain connections," Isacson said. "We do not think LINGO-1 is the only way to maintain the structure of the cells, but I think we have shown an important insight. There is also a possible link between LRRK-2 and LINGO-1. They appear to be working together and we are looking at that."

[ZucchiniFlower]

I wonder if there is a mutation linked to Lingo-1 like there is for LRRK2. Is there a Lingo-2?

[olsen]

hi zucchini, the entirety of my knowledge of Lingo-1 (in addition to the first post)--appears important in neuronal plasticity

Neuronal activity-induced regulation of Lingo-1.

REGENERATION AND TRANSPLANTATION

Neuroreport. 15(15):2397-2400, October 25, 2004.
Trifunovski, Alexandra CA; Josephson, Anna; Ringman, Andreas; Brene, Stefan; Spenger, Christian; Olson, Lars
Abstract:
Axonal regeneration after injury can be limited in the adult CNS by the presence of inhibitory proteins such as Nogo. Nogo binds to a receptor complex that consists of Nogo receptor (NgR), p75NTR, and Lingo-1. Nogo binding activates RhoA, which inhibits axonal outgrowth. Here we assessed Lingo-1 and NgR mRNA levels after delivery of BDNF into the rat hippocampal formation, Lingo-1 mRNA levels in rats subjected to kainic acid (KA) and running in running wheels. Lingo-1 mRNA was not changed by running. However, we found that Lingo-1 mRNA was strongly up-regulated while NgR mRNA was down-regulated in the dentate gyrus in both the BDNF and the KA experiments. Our data demonstrate inverse regulation of NgR and Lingo-1 in these situations, suggesting that Lingo-1 up-regulation is one characteristic of activity-induced neural plasticity responses.

(C) 2004 Lippincott Williams & Wilkins, Inc.

[ZucchiniFlower]

Nature Neuroscience 8, 745 - 751 (2005)
Published online: 15 May 2005; | doi:10.1038/nn1460

LINGO-1 negatively regulates myelination by oligodendrocytes

Sha Mi1, Robert H Miller2,, etc

Correspondence should be addressed to Sha Mi sha.mi@biogenidec.com


The control of myelination by oligodendrocytes in the CNS is poorly understood. Here we show that LINGO-1 is an important negative regulator of this critical process. LINGO-1 is expressed in oligodendrocytes. Attenuation of its function by dominant-negative LINGO-1, LINGO-1 RNA-mediated interference (RNAi) or soluble human LINGO-1 (LINGO-1-Fc) leads to differentiation and increased myelination competence. Attenuation of LINGO-1 results in downregulation of RhoA activity, which has been implicated in oligodendrocyte differentiation. Conversely, overexpression of LINGO-1 leads to activation of RhoA and inhibition of oligodendrocyte differentiation and myelination. Treatment of oligodendrocyte and neuron cocultures with LINGO-1-Fc resulted in highly developed myelinated axons that have internodes and well-defined nodes of Ranvier.

The contribution of LINGO-1 to myelination was verified in vivo through the analysis of LINGO-1 knockout mice. The ability to recapitulate CNS myelination in vitro using LINGO-1 antagonists and the in vivo effects seen in the LINGO-1 knockout indicate that LINGO-1 signaling may be critical for CNS myelination.

[ZucchiniFlower]

doi:10.1016/j.cub.2005.04.002 How to Cite or Link Using DOI (Opens New Window)
Copyright © 2005 Elsevier Ltd All rights reserved.

Dispatch

Axon Regeneration: It’s Getting Crowded at the Gates of TROY

Wim J. MandemakersCorresponding Author Contact Information, E-mail The Corresponding Author and Ben A. Barres
Stanford University School of Medicine, Neurobiology Department, Sherman Fairchild Science Building, Room D129, 299 Campus Drive, Stanford, California 94305-5125, USA.

Available online 26 April 2005.



A novel neuronal receptor complex that mediates myelin’s inhibitory action on nerve fiber regeneration has at last been identified. This discovery could be an important step towards promoting nerve regeneration after stroke or spinal cord injury.


Most tissues in our bodies have an astonishing ability to repair themselves after injury, but a notable exception is the adult mammalian central nervous system (CNS) — the brain and spinal cord — which has little innate capacity for repair. When the axons of CNS neurons are severed they are unable to regenerate, accounting for the devastating impairment induced by spinal cord injury, stroke and many other neurological conditions. What accounts for the failure of the CNS to regenerate? One crucial factor is that the adult CNS environment is strongly inhibitory to regenerating axons. In particular, much recent attention has been focused on the powerful inhibition of degenerating myelin.

How does myelin inhibit the growth of CNS axons? Three different myelin proteins have been identified that are strongly inhibitory to most types of CNS neurons: Nogo-A, myelin associated glycoprotein (MAG) and oligodendrocyte myelin glycoprotein (OMgp) [1]. Remarkably, all three of these myelin-associated inhibitor factors are able to bind to and activate the same axonal multi-protein receptor complex. The proteins that generate this receptor complex are the ligand binding Nogo-66 receptor (NgR1) and two signal transducing binding partners, the p75 neurotrophin receptor (p75) and the LRR and Ig domain-containing, Nogo receptor-interacting protein (LINGO-1) [2 and 3]. Interaction of myelin-associated inhibitors with the p75/NgR1/LINGO-1 complex activates the small GTPase RhoA, which rigidifies the actin cytoskeleton, thereby causing growth cone collapse [4]. The potential contribution of this signaling pathway to CNS regenerative failure is clearly shown by the ability of RhoA blockade to promote axon regeneration in vivo after injury [5 and 6].

Though the identification of the p75/NgR1/LINGO-1 receptor complex has been an exciting advance, a perplexing mystery has remained. Although NgR1 and LINGO-1 are widely expressed throughout the CNS, p75 is for the most part down-regulated during development so that it is not widely expressed in the adult CNS. Many CNS neuron types that are inhibited by myelin, such as retinal ganglion cells, do not express p75 in the adult CNS [7]. Furthermore, although neurons isolated from p75 mutant mice are less inhibited by myelin inhibitors in vitro, a significant inhibitory activity remains [8], and axon regeneration after spinal cord injury is not enhanced in these mice [9].

Might there be a p75 homologue that is more widely expressed in the adult CNS that could substitute for p75 in this receptor complex? As p75 is a member of the extensive TNF receptor family, two research groups [10 and 11] independently set out to test this hypothesis. In fact, several members of the TNF receptor family have already been reported to be widely expressed in the CNS including TROY, CD40, DR6, Fn14, TNFR1 and TNFR2. Using either ELISA or cell binding assays, both groups [10 and 11] found that, of these proteins, only TROY could interact with NgR1 and that its interaction was nearly eight-fold stronger than the interaction between p75 and NgR1. And by immunoprecipitation, both groups demonstrated that TROY is able to form a complex with NgR1 and LINGO-1 [10 and 11].

So is TROY a functional homolog of p75? To find out, both groups [10 and 11] next tested whether expression of the TROY/NgR1/LINGO-1 complex in non-neural cells can activate RhoA in response to myelin-associated inhibitor factor binding. They found strong RhoA activation, confirming that TROY can substitute for p75 in the RhoA signaling pathway.

In elegant experiments, both groups [10 and 11] also showed that TROY regulates neurite outgrowth of dorsal root ganglion neurons and cerebellar granule neurons grown on myelin, OMgp and Nogo-66 in vitro. Increasing neuronal TROY levels by expression of full-length TROY from a viral vector enhanced myelin inhibitor-mediated inhibition of neurite outgrowth, whereas expression of a truncated dominant negative TROY (DN-TROY) significantly lessened this inhibition. Moreover, interfering with the interaction between myelin-associated inhibitors and the TROY/NgR1/LINGO-1 complex by addition of soluble TROY fusion proteins to the culture media greatly promoted neurite outgrowth.

Taken together, these results indicate that TROY transduces myelin-mediated inhibition of neurite outgrowth, provide evidence that TROY can functionally replace p75 in the NgR1 complex, and add TROY to the rapidly growing list of proteins that mediate axon inhibition by activating RhoA (Figure 1).


Display Full Size version of this image (49K)

Figure 1. TROY is a novel NgR1 coreceptor and mediates CNS myelin mediated axon outgrowth inhibition.

The myelin associated inhibitor factors Nogo-66, MAG and OMgp block regeneration of axons by binding to a shared receptor NgR1. In addition to an interaction between NgR1, LINGO-1 and p75, a newly identified receptor complex consisting of NgR1, LINGO-1 and TROY can transduce signaling upon binding of myelin associated inhibitor factor to NgR1, leading to RhoA activation and axon outgrowth inhibition. Blocking the formation of these receptor complexes by addition of dominant negative (DN) forms of either p75 or TROY (DN-p75, DN-TROY) antagonizes the axon outgrowth inhibitory effect of myelin associated inhibitor factor and myelin leading to greatly improved neurite outgrowth of dorsal root ganglion and cerebellar granule neurons in vitro.

Is TROY responsible for the residual inhibition of neurite outgrowth in response to myelin inhibitors observed in neurons lacking p75 function in vitro? To address this question, Park et al. [10] very elegantly demonstrated that dorsal root ganglion neurons can be subdivided into p75-expressing and non-expressing neurons, which can be distinguished by staining with isolectin B4 (IB4). Dorsal root ganglion neurons expressing IB4 do not express p75 and vice versa. Both populations are responsive to myelin-associated inhibitors, indicating that p75 is not essential for myelin-mediated inhibition of neurite outgrowth. But DN-TROY dramatically enhances neurite outgrowth from both IB4+ and IB4– dorsal root ganglion neurons cultured on myelin inhibitor substrates, and IB4– neurons isolated from p75-deficient mice still show a partial response to myelin inhibitors [10].

Interestingly, however, even in the absence of both TROY and p75 function, neurite lengths were still shorter than control, suggesting the possibility that additional, p75/TROY-independent, signaling pathways may yet exist that transduce myelin-mediated inhibition of neurite outgrowth. Nevertheless, introduction of full length TROY (FL-TROY) enhanced responsiveness of p75-deficient IB4– neurons, further substantiating that TROY is a functional homolog of p75 in transducing the inhibitory signals of myelin-associated inhibitors [10].

To demonstrate conclusively that TROY has a role in transducing inhibition of neurite outgrowth by myelin inhibitors, Shao et al.[11] generated TROY-deficient mice. These mice are viable and exhibit no obvious anomalies. As expected, dorsal root ganglion neurons isolated from TROY-deficient mice were less sensitive to myelin-associated neurite outgrowth inhibitors, but they were only able to completely overcome inhibition at low concentrations of Nogo-66, OMgp and myelin. Presumably much of the residual neurite outgrowth inhibition at higher myelin inhibitor concentrations is mediated by p75. From these exciting new results it can be concluded that TROY plays an important role in mediating the inhibitory effect of myelin inhibitors via the TROY/NgR1/LINGO-1 complex, and can functionally replace p75.

What implications does the discovery of this new receptor complex have for promoting CNS regeneration in vivo? The functional redundancy of p75 and TROY might very well explain the lack of improved regeneration after spinal cord injury in p75 knockout mice [9]. Thus, whether TROY-deficient mice will display enhanced regeneration is now a very exciting question. As p75 is widely upregulated after injury, however, p75 might actually be functionally redundant in TROY knockout animals [12]. This issue will no doubt soon be addressed by the generation of TROY/p75 double-knockout mice. That these mice will display enhanced regeneration is far from certain, as local administration of a p75 dominant-negative (DN-p75), which also blocks TROY, does not improve regeneration within the injured spinal cord [9 and 10]. Not only is it possible that additional TNF-receptor family members are involved, but also other NgR and LINGO protein family members (NgR2, NgR3, LINGO-2, LINGO-3 and LINGO-4) may play a role in myelin induced axon outgrowth inhibition [13, 14, 15, 16, 17 and 18]. Furthermore, additional myelin inhibitory proteins, such as Sema4D and the amino-terminal domain of Nogo-A, as well as unidentified myelin-associated inhibitors and their receptors, might mediate axon outgrowth inhibition independent of NgR1 receptor complexes [19 and 20].

Despite all these unanswered questions, the identification of TROY is a major step forward in understanding how myelin inhibits axon regeneration, providing new insight into the signaling pathways involved in regenerative failure and new avenues for how repair may be stimulated.

http://www.sciencedirect.com/science...65392b05f71bfd