Experimental Immunotherapy May Slow Parkinson’s Disease Progression, Researchers Say

Experimental Immunotherapy May Slow Parkinson’s Disease Progression, Researchers Say

Toxic aggregates of the alpha-synuclein protein, which are known to cause Parkinson’s disease, can spread from one brain cell to the other, causing the disease to progress. In a new study, researchers have identified a protein that allows this mechanism to occur, posing itself as a target to stop the progression of the disease.

The study, “Pathological α-synuclein transmission initiated by binding lymphocyte-activation gene 3,” published in Science, suggests that an immunotherapy already in clinical trials could be tested as a way to slow the progression of Parkinson’s disease.

Abnormal aggregates of alpha-synuclein in the brain tissue are believed to be one of the causes of brain cells’ death.

Previous work suggested that Parkinson’s disease progression was due to the spread of alpha-synuclein aggregates from one brain cell to another, explaining how brain areas responsible for memory and reasoning, and not only those responsible for movement and basic functions, also became affected as the disease progresses.

To target this process, Dr. Ted Dawson, MD, PhD, director of the Institute for Cell Engineering at the Johns Hopkins University School of Medicine, teamed up with Valina Dawson, PhD, professor of neurology, and Han Seok Ko, PhD, assistant professor of neurology, to investigate how the alpha-synuclein aggregates could enter cells.

The researchers identified a type of human brain cancer cells, grown in the laboratory, that did not allow alpha-synuclein aggregates to enter. More careful analyses showed that these cells were lacking three specific transmembrane proteins. These proteins are typically found on the outside of cells and are responsible for admitting specific proteins inside cells. One of the identified transmembrane proteins, called LAG3, showed a particular preference for alpha-synuclein aggregates over nonclumped alpha-synuclein.

Since the absence of LAG3 in the brain cells of Parkinson’s disease animal models protected the mice from the effects of alpha-synuclein aggregates, the researchers proceeded to investigate whether LAG3 blocking therapies could be used to prevent these aggregates to spread.

Importantly, the investigators found that these LAG3 blocking therapies could also prevent the spreading of alpha-synuclein aggregates in cultured neurons, revealing that LAG3 inhibitors may also be a promising therapeutic approach for Parkinson’s patients.

LAG3 inhibitors, which have recently emerged as promising immune checkpoint inhibitors that may be better alternatives or work in synergy with currently approved checkpoint inhibitors, are currently in clinical trials for a variety of solid and hematologic tumors. If the ongoing clinical trials demonstrate the drugs’ safety, the process of testing them as therapeutics for Parkinson’s disease might be sped up, Dawson said.

“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,” says Xiaobo Mao, PhD, first author on the study. Nevertheless, more studies on LAG3 function are required.

One comment

  1. John Hop says:

    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

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