Interfering in the Spread of Alpha-Synuclein to Treat Synucleopathies

Researchers here demonstrate a method of interfering in the spread of alpha-synuclein aggregates, an approach that may slow the progression of synucleopathies such as Parkinson's disease. Like a number of other age-related neurodegenerative conditions, these are associated with and probably driven by the growing presence of specific misfolded or damaged proteins. The ideal approach is to find ways to safely remove these proteins, or understand and resolve the underlying reasons for their accumulation, both of which are paths that are so far proving to be more challenging than expected. Much of the research community remains focused on attempts to alter the late stage biochemistry of disease progression, however, as is the case here, rather than taking aim at root causes. This can be effective, but it is usually going to be much harder to prevent pathology without fixing the root causes than it is by going after those root causes.

Researchers report they have identified a protein that enables a toxic natural aggregate to spread from cell to cell in a mammal's brain - and a way to block that protein's action. The new findings hinge on how aggregates of alpha-synuclein protein enter brain cells. Abnormal clumps of alpha-synuclein protein are often found in autopsies of people with Parkinson's disease and are thought to cause the death of dopamine-producing brain cells. A few years ago, researchers published evidence for a novel theory that Parkinson's disease progresses as alpha-synuclein aggregates spread from brain cell to brain cell, inducing previously normal alpha-synuclein protein to aggregate, and gradually move from the "lower" brain structures responsible for movement and basic functions to "higher" areas associated with processes like memory and reasoning. "There was a lot of skepticism, but then other labs showed alpha-synuclein might spread from cell to cell."

The researchers knew they were looking for a certain kind of protein called a transmembrane receptor, which is found on the outside of a cell and works like a lock in a door, admitting only proteins with the right "key." They first found a type of cells alpha-synuclein aggregates could not enter - a line of human brain cancer cells grown in the laboratory. The next step was to add genes for transmembrane receptors one by one to the cells and see whether any of them allowed the aggregates in. Three of the proteins did, and one, LAG3, had a heavy preference for latching on to alpha-synuclein aggregates over nonclumped alpha-synuclein. The team next bred mice that lacked the gene for LAG3 and injected them with alpha-synuclein aggregates. "Typical mice develop Parkinson's-like symptoms soon after they're injected, and within six months, half of their dopamine-making neurons die. But mice without LAG3 were almost completely protected from these effects."

Antibodies that blocked LAG3 had similar protective effects in cultured neurons, the researchers found. "We were excited to find not only how alpha-synuclein aggregates spread through the brain, but also that their progress could be blocked by existing antibodies." Antibodies targeting LAG3 are already in clinical trials to test whether they can beef up the immune system during chemotherapy. If those trials demonstrate the drugs' safety, the process of testing them as therapeutics for Parkinsons' disease might be sped up, he says. For now, the research team is planning to continue testing LAG3 antibodies in mice and to further explore LAG3's function.

Link: https://www.eurekalert.org/pub_releases/2016-10/jhm-nts101116.php

Comments

The expression of LAG3 on neurons instead of astrocytes, microglia or oligodendrocytes, is extremely confusing and contradictory to all the publicly available literatures and database. Even the reference (Workman CJ et al., Eur J Immunol. 2002) provided by Prof. Dr. Ted Dawson at alzforum (http://www.alzforum.org/news/research-news/immune-receptor-may-smuggle-synuclein-neurons-hasten-proteopathy) is absolutely against Dr. Dawson his own claim. The LAG3 mRNA expression is restricted to sparse cells in the adult brain cortex, and defined tracts at the base of the cerebellum and in the choroid plexus of day 7 postnatal brain. Please see below,

'In situ hybridization analysis of adult brain has shown that LAG-3 mRNA is expressed in a restricted population of sparse cells throughout the cortex, but absent from the cerebellum. In contrast, very bright and dramatic hybridization was observed in day 7 postnatal brain, in defined tracts at the base of the cerebellum, in the developing white matter and in the choroid plexus. Although CD223 mRNA could not be found in human adult brain, this could be age related (Triebel, F., et al. 1990).'

This paper (Workman CJ et al., Eur J Immunol. 2002) even also says that CD223 (LAG3) mRNA could not be found in human adult brain, if the NON-brain expression of LAG3 is true, the finding by Mao and his colleagues will be meaningless. Should not the authors do more solid experiment to confirm the expression in neurons instead of astrocytes or microglia?

Also, from 'Immune Mediators of Central Nervous System Demyelination and Remyelination', a dissertation submitted to the faculty of the University of North Carolina at Chapel Hill, it shows LAG3 on a subpopulation of astrocytes, oligodendrocyte precursor cells, (https://cdr.lib.unc.edu/indexablecontent/uuid:c751db89-2ae7-4225-88e0-c62eba36f255).This expression pattern is very much fit to Jia Qian Wu, Ben A Barres et al., paper, their RNAseq data clearly show LAG3 express on microglia, and oligodendrocyte precursors (Zhang Y et al, 2014).

There are some other evidence showing that LAG3 is not expressed on human neurons, for example, http://www.proteinatlas.org/ENSG00000089692-LAG3/tissue

Reference:
1. Workman CJ, Rice DS, Dugger KJ, Kurschner C, Vignali DA. Phenotypic analysis of the murine CD4-related glycoprotein, CD223 (LAG-3). Eur J Immunol. 2002 Aug;32(8):2255-63. PubMed.
2. Triebel, F., Jitsukawa, S., Baixeras, E., Roman-Roman, S., Genevee, C., Viegas-Pequignot, E. and Hercend, T., LAG-3, a novel lymphocyte activation gene closely related to CD4. J. Exp. Med. 1990. 171: 1393-1405.
3. https://cdr.lib.unc.edu/indexablecontent/uuid:c751db89-2ae7-4225-88e0-c62eba36f255
4. Zhang Y, Chen K, Sloan SA, Bennett ML, Scholze AR, O'Keeffe S, Phatnani HP, Guarnieri P, Caneda C, Ruderisch N, Deng S, Liddelow SA, Zhang C, Daneman R, Maniatis T, Barres BA, Wu JQ. An RNA-sequencing transcriptome and splicing database of glia, neurons, and vascular cells of the cerebral cortex. J Neurosci. 2014 Sep 3;34(36):11929-47. doi: 10.1523/JNEUROSCI.1860-14.2014.
5. http://www.proteinatlas.org/ENSG00000089692-LAG3/tissue

Posted by: John Hop at September 22nd, 2017 9:03 PM
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