Inflammation May Increase FTD Risk, Scientists Say

Inflammation in the brain is a key sign of neurodegenerative diseases including ALS and FTD. But whether this immune response contributes or is a consequence of these diseases remains hotly debated.

The immune system: In the driver’s seat? Changes in key microglial genes including LRRK2 kinase increase the risk of developing FTD and immune-mediated diseases according to a GWAS analysis suggesting common underlying mechanisms. The findings build on recent results, led by Mount Sinai’s Inga Peter in New York, which found that variants of LRRK2 influenced the likelihood of developing either Parkinson’s or Crohn’s disease (see January 2018 news; Hui et al., 2018). LRRK2 inhibitors, developed by Denali Therapeutics in San Francisco, are currently being tested in Europe at the phase 1 stage in healthy volunteers. [Courtesy of Broce et al., 2018, PLOS Medicine. CC BY License.]

Now, a research team led by University of California-San Francisco’s Leo Sugrue reports that inflammation may increase the susceptibility of developing FTD (Broce et al., 2018; see also Ferrari et al., 2014). The findings build on previous studies, led by University of California-San Francisco’s Zachary Miller, which found that people with FTD with TDP-43 pathology were more likely to have an autoimmune disease (Miller et al., 2016; Miller et al., 2013).

The findings appeared on January 9 in PLOS Medicine.

The researchers found, based on a genome-wide association analysis, significant genetic overlap between FTD and immune-related diseases including rheumatoid arthritis and ulcerative colitis. What’s more, these shared disease-linked SNPs cluster in genes important in the function of microglia -the same immune cells that may mediate the neuroinflammation increasingly implicated in the pathogenesis of C9orf72 ALS and FTD (Umoh et al., 2017; O’Rourke et al., 2016; for review, see Lall and Baloh, 2017).

The approach, known as “pleiotropy” analysis, suggests that these diseases may share common immune-mediated mechanisms.

The results come at the heels of previous preclinical studies, led by University College London’s Adrian Isaacs in England, which found that the activation of microglia could be detected prior to neuronal loss in a mouse model of CHMP2B-linked FTD (see February 2017 news; Clayton et al., 2017).

Together, the findings add to growing evidence that inflammation may contribute to the onset of at least some forms of FTD. Therefore, emerging treatment strategies that reduce this inflammation may be a potential strategy to tackle them.

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To learn more about the emerging role of inflammation in the onset of neurodegenerative diseases including ALS, check out Early Inflammation May Play A Role in FTD.

Featured Papers

Broce I, Karch CM, Wen N, Fan CC, Wang Y, Hong Tan C, Kouri N, Ross OA, Höglinger GU, Muller U, Hardy J; International FTD-Genomics Consortium, Momeni P, Hess CP, Dillon WP, Miller ZA, Bonham LW, Rabinovici GD, Rosen HJ, Schellenberg GD, Franke A, Karlsen TH, Veldink JH, Ferrari R, Yokoyama JS, Miller BL, Andreassen OA, Dale AM, Desikan RS, Sugrue LP. Immune-related genetic enrichment in frontotemporal dementia: An analysis of genome-wide association studies. PLoS Med. 2018 Jan 9;15(1):e1002487. [PubMed].

Umoh ME, Dammer EB, Dai J, Duong DM, Lah JJ, Levey AI, Gearing M, Glass JD, Seyfried NT. A proteomic network approach across the ALS-FTD disease spectrum resolves clinical phenotypes and genetic vulnerability in human brain. EMBO Mol Med. 2018 Jan;10(1):48-62. [PubMed].

References

Miller ZA, Sturm VE, Camsari GB, Karydas A, Yokoyama JS, Grinberg LT, Boxer AL, Rosen HJ, Rankin KP, Gorno-Tempini ML, Coppola G, Geschwind DH, Rademakers R, Seeley WW, Graff-Radford NR, Miller BL. Increased prevalence of autoimmune disease within C9 and FTD/MND cohorts: Completing the picture. Neurol Neuroimmunol Neuroinflamm. 2016 Oct 28;3(6):e301. [PubMed].

Miller ZA, Rankin KP, Graff-Radford NR, Takada LT, Sturm VE, Cleveland CM, Criswell LA, Jaeger PA, Stan T, Heggeli KA, Hsu SC, Karydas A, Khan BK, Grinberg LT, Gorno-Tempini ML, Boxer AL, Rosen HJ, Kramer JH, Coppola G, Geschwind DH, Rademakers R, Seeley WW, Wyss-Coray T, Miller BL. TDP-43 frontotemporal lobar degeneration and autoimmune disease. J Neurol Neurosurg Psychiatry. 2013 Sep;84(9):956-62. [PubMed].

Clayton EL, Mancuso R, Nielsen TT, Mizielinska S, Holmes H, Powell N, Norona F, Larsen JO, Milioto C, Wilson KM, Lythgoe MF, Ourselin S, Nielsen JE, Johannsen P, Holm I, Collinge J; FReJA, Oliver PL, Gomez-Nicola D, Isaacs AM. Early microgliosis precedes neuronal loss and behavioural impairment in mice with a frontotemporal dementia-causing CHMP2B mutation. Hum Mol Genet. 2017 Mar 1;26(5):873-887. [PubMed].

O’Rourke JG, Bogdanik L, Yáñez A, Lall D, Wolf AJ, Muhammad AK, Ho R, Carmona S, Vit JP, Zarrow J, Kim KJ, Bell S, Harms MB, Miller TM, Dangler CA, Underhill DM, Goodridge HS, Lutz CM, Baloh RH. C9orf72 is required for proper macrophage and microglial function in mice. Science. 2016 Mar 18;351(6279):1324-9. [PubMed].

Further Reading

Lall, D, Baloh, RH. Microglia and C9orf72 in neuroinflammation and ALS and frontotemporal dementia. J Clin Invest. 2017 Sep 1;127(9):3250-3258. [PubMed].

Hui KY, Fernandez-Hernandez H, Hu J, Schaffner A, Pankratz N, Hsu NY, Chuang LS, Carmi S, Villaverde N, Li X, Rivas M, Levine AP, Bao X, Labrias PR, Haritunians T, Ruane D, Gettler K, Chen E, Li D, Schiff ER, Pontikos N, Barzilai N, Brant SR, Bressman S, Cheifetz AS, Clark LN, Daly MJ, Desnick RJ, Duerr RH, Katz S, Lencz T, Myers RH, Ostrer H, Ozelius L, Payami H, Peter Y, Rioux JD, Segal AW, Scott WK, Silverberg MS, Vance JM, Ubarretxena-Belandia I, Foroud T, Atzmon G, Pe’er I, Ioannou Y, McGovern DPB, Yue Z, Schadt EE, Cho JH, Peter I. Functional variants in the LRRK2 gene confer shared effects on risk for Crohn’s disease and Parkinson’s disease.Sci Transl Med. 2018 Jan 10;10(423). [PubMed].

 

disease-als disease-ftd inflammation LRRK2 microglia neuroinflammation
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