Does Progranulin Play Both Sides in AD and FTD?

Mutations that cause frontotemporal dementia may also predispose carriers to Alzheimer’s dementia, according to a paper in the April 22 JAMA Neurology online. Previous genetic studies have suggested that progranulin mutations increase risk for AD (Brouwers et al., 2008; Fenoglio et al., 2009; Lee et al., 2011); the current study solidifies the association by confirming amyloid pathology in two cases. Nonetheless, the possibility remains that their Alzheimer’s is unrelated to progranulin genotype. In small studies such as this, it is difficult to prove beyond a doubt that a genetic association with disease is truly the cause of symptoms.

Researchers led by Gil Rabinovici of the University of California, San Francisco, identified the cases. One was a man who developed typical AD symptoms at age 62; the other a woman whose speech impairment, of a type often associated with Alzheimer’s, began when she was 53. Both carried one copy of ApoE4, as well as a progranulin mutation. While progranulin is more commonly linked to frontotemporal dementia (FTD), Alzheimer’s is not entirely uncommon in mutation carriers, said first author David Perry, also at UCSF. According to the literature, 9-17 percent of people with progranulin mutations have AD-like symptoms (Le Ber et al., 2008; Rademakers et al., 2007). Both people in the study also had family histories of FTD.

An Alzheimer’s diagnosis requires amyloid in the brain, while FTD frequently means inclusions of the protein TDP-43. On autopsy of the woman, who died at age 55, both pathologies were present. In the man, imaging with the amyloid tracer Pittsburgh Compound B confirmed cortical amyloid. Since he still lives, the researchers do not know if he has TDP-43 pathology as well. “Their clinical syndrome, and their imaging and pathology data, are consistent with Alzheimer’s disease,” Perry said. “I think the progranulin mutation may be increasing their risk of getting Alzheimer’s.”

Then again, it could be that the participants would have developed Alzheimer’s regardless of their progranulin genotype. Some purported genetic links turn out to be wrong (see ARF Webinar). However, the young age of the people in the study argues against coincidence, commented Rita Guerreiro of University College London in the U.K., who was not involved in this work (see comment below). The likelihood of amyloid pathology and sporadic AD symptoms in people in their fifties and sixties is quite low, Perry said, even given their ApoE status.

Guerreiro noted that she often finds mismatches between genetics and diagnosis. For example, she and her colleagues recently discovered that homozygous mutations in TREM2, which cause a rare bone disease, also cause FTD (see ARF related news story on Guerreiro et al., 2012), while mutations in one copy of the gene boost the risk for AD (see ARF related news story on Guerreiro et al., 2013; Jonsson et al., 2013). “These diseases all seem to be related somehow,” she said (see ARF related news story). She recommends sequencing several genes, or better yet, the whole exome, to find the genetic root for a person’s disease.

Progranulin mutations lead to a 50 percent drop in the protein's concentration. How could that cause AD or FTD? Perry suspects that the deficiency promotes inflammation, rendering the brain prone to degeneration and dementia in general (see ARF related news story on Martens et al., 2012). Inflammation and activation of TNF-α has been linked to cognitive decline, extra amyloid production, and less microglial engulfment of amyloid in mice (Holmes, 2012; Yamamoto et al., 2007; see ARF related news story on Hickman et al., 2008). Which specific dementia arises might be determined by other genetic factors, suggested Mikko Hiltunen of the University of Eastern Finland in Kuopio, who was not involved in the study (see comment below). Perry added that if AD and FTD do share molecular roots, then they might share treatment targets as well.—Amber Dance

Comments

  1. These are very interesting data, adding to the many cases of potential pleiotropy that we are starting to see more often by applying next-generation sequencing to the study of neurodegenerative diseases.

    Before the availability of these technologies, sequencing would be performed only in the genes known to be associated with a specific clinical picture. Now what we are seeing is that some of these cases have mutations in genes that haven't been directly associated with that specific clinical entity, but rather with a similar disease, in this case, another form of dementia.

    The early age at onset for these cases (especially case 2) makes it less probable that AD is co-occurring with FTD just by chance, and suggests the existence of common molecular pathways between FTD and AD. We can easily establish a parallel with TREM2 or C9ORF72. In the TREM2 gene, homozygous mutations were initially identified to cause Nasu-Hakola disease; later, the same types of mutations were found to cause FTD without any bone symptoms and, more recently, heterozygous variants were shown to increase the risk for AD. Similarly the expansion on C9ORF72 was initially found in cases diagnosed with ALS, FTD, or ALS/FTD, providing genetic evidence that these diseases are most likely part of a pathological spectrum.

    Interestingly, TREM2 is also involved in inflammatory processes, and the roles of microglia and inflammatory cellular status are becoming more central as molecular pathological pathways for different dementias.

    These results clearly stress the importance of taking a non-restrictive approach to the screening of genetic variants, which can now be achieved by using targeted sequencing panels or exome/genome sequencing. The identification of more cases like these will allow the study of previously unrecognized associations between genetic variability in the different genes involved in these disorders.

    View all comments by Rita Guerreiro

  2. Perry et al. have identified two patients with Alzheimer’s disease (AD) pathology who also have a mutation in the progranulin (GRN) gene. This is an extremely important finding, considering that the GRN mutations are known to cause the autosomal-dominant form of frontotemporal dementia (FTD) through the haploinsufficiency of functional progranulin. This observation is consistent with previous work, which has suggested that certain variants of GRN, such as SNP rs5848, increase the risk of AD in different AD cohorts. Thus, it is possible that the mutations/variants in GRN may also play a role as risk factors in AD. However, that both patients also harbored the ApoE4 allele, which is the most prominent genetic risk factor for AD, emphasizes the importance of conducting further studies before making firm conclusions about GRN in AD.

    View all comments by Mikko Hiltunen

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References

Webinar Citations

  1. Weeding Mendel’s Garden: Can We Hoe Dubious Genetic Associations?

News Citations

  1. Mutations in TREM2 Cause Frontotemporal Dementia
  2. Enter the New Alzheimer’s Gene: TREM2 Variant Triples Risk
  3. Spectrum of Neurodegeneration Comes to the Fore
  4. Microglial Progranulin Douses Neural Inflammation
  5. Why Good Microglia Turn Bad—A Matter of Timing?

Paper Citations

  1. Brouwers N, Sleegers K, Engelborghs S, Maurer-Stroh S, Gijselinck I, van der Zee J, Pickut BA, Van den Broeck M, Mattheijssens M, Peeters K, Schymkowitz J, Rousseau F, Martin JJ, Cruts M, De Deyn PP, Van Broeckhoven C. Genetic variability in progranulin contributes to risk for clinically diagnosed Alzheimer disease. Neurology. 2008 Aug 26;71(9):656-64. PubMed.
  2. Fenoglio C, Galimberti D, Cortini F, Kauwe JS, Cruchaga C, Venturelli E, Villa C, Serpente M, Scalabrini D, Mayo K, Piccio LM, Clerici F, Albani D, Mariani C, Forloni G, Bresolin N, Goate AM, Scarpini E. Rs5848 variant influences GRN mRNA levels in brain and peripheral mononuclear cells in patients with Alzheimer's disease. J Alzheimers Dis. 2009;18(3):603-12. PubMed.
  3. Lee MJ, Chen TF, Cheng TW, Chiu MJ. rs5848 variant of progranulin gene is a risk of Alzheimer's disease in the Taiwanese population. Neurodegener Dis. 2011;8(4):216-20. PubMed.
  4. Le Ber I, Camuzat A, Hannequin D, Pasquier F, Guedj E, Rovelet-Lecrux A, Hahn-Barma V, van der Zee J, Clot F, Bakchine S, Puel M, Ghanim M, Lacomblez L, Mikol J, Deramecourt V, Lejeune P, de la Sayette V, Belliard S, Vercelletto M, Meyrignac C, Van Broeckhoven C, Lambert JC, Verpillat P, Campion D, Habert MO, Dubois B, Brice A, French research network on FTD/FTD-MND. Phenotype variability in progranulin mutation carriers: a clinical, neuropsychological, imaging and genetic study. Brain. 2008 Mar;131(Pt 3):732-46. Epub 2008 Feb 1 PubMed.
  5. Rademakers R, Baker M, Gass J, Adamson J, Huey ED, Momeni P, Spina S, Coppola G, Karydas AM, Stewart H, Johnson N, Hsiung GY, Kelley B, Kuntz K, Steinbart E, Wood EM, Yu CE, Josephs K, Sorenson E, Womack KB, Weintraub S, Pickering-Brown SM, Schofield PR, Brooks WS, Van Deerlin VM, Snowden J, Clark CM, Kertesz A, Boylan K, Ghetti B, Neary D, Schellenberg GD, Beach TG, Mesulam M, Mann D, Grafman J, Mackenzie IR, Feldman H, Bird T, Petersen R, Knopman D, Boeve B, Geschwind DH, Miller B, Wszolek Z, Lippa C, Bigio EH, Dickson D, Graff-Radford N, Hutton M. Phenotypic variability associated with progranulin haploinsufficiency in patients with the common 1477C-->T (Arg493X) mutation: an international initiative. Lancet Neurol. 2007 Oct;6(10):857-68. PubMed.
  6. Guerreiro RJ, Lohmann E, Brás JM, Gibbs JR, Rohrer JD, Gurunlian N, Dursun B, Bilgic B, Hanagasi H, Gurvit H, Emre M, Singleton A, Hardy J. Using exome sequencing to reveal mutations in TREM2 presenting as a frontotemporal dementia-like syndrome without bone involvement. JAMA Neurol. 2013 Jan;70(1):78-84. PubMed.
  7. Guerreiro R, Wojtas A, Bras J, Carrasquillo M, Rogaeva E, Majounie E, Cruchaga C, Sassi C, Kauwe JS, Younkin S, Hazrati L, Collinge J, Pocock J, Lashley T, Williams J, Lambert JC, Amouyel P, Goate A, Rademakers R, Morgan K, Powell J, St George-Hyslop P, Singleton A, Hardy J, Alzheimer Genetic Analysis Group. TREM2 variants in Alzheimer's disease. N Engl J Med. 2013 Jan 10;368(2):117-27. Epub 2012 Nov 14 PubMed.
  8. Jonsson T, Stefansson H, Steinberg S, Jonsdottir I, Jonsson PV, Snaedal J, Bjornsson S, Huttenlocher J, Levey AI, Lah JJ, Rujescu D, Hampel H, Giegling I, Andreassen OA, Engedal K, Ulstein I, Djurovic S, Ibrahim-Verbaas C, Hofman A, Ikram MA, van Duijn CM, Thorsteinsdottir U, Kong A, Stefansson K. Variant of TREM2 associated with the risk of Alzheimer's disease. N Engl J Med. 2013 Jan 10;368(2):107-16. Epub 2012 Nov 14 PubMed.
  9. Martens LH, Zhang J, Barmada SJ, Zhou P, Kamiya S, Sun B, Min SW, Gan L, Finkbeiner S, Huang EJ, Farese RV. Progranulin deficiency promotes neuroinflammation and neuron loss following toxin-induced injury. J Clin Invest. 2012 Nov 1;122(11):3955-9. PubMed.
  10. Holmes C. Systemic inflammation and Alzheimer's Disease. Neuropathol Appl Neurobiol. 2012 Oct 10; PubMed.
  11. Yamamoto M, Kiyota T, Horiba M, Buescher JL, Walsh SM, Gendelman HE, Ikezu T. Interferon-gamma and tumor necrosis factor-alpha regulate amyloid-beta plaque deposition and beta-secretase expression in Swedish mutant APP transgenic mice. Am J Pathol. 2007 Feb;170(2):680-92. PubMed.
  12. Hickman SE, Allison EK, El Khoury J. Microglial dysfunction and defective beta-amyloid clearance pathways in aging Alzheimer's disease mice. J Neurosci. 2008 Aug 13;28(33):8354-60. PubMed.

Further Reading

Papers

  1. Ward ME, Miller BL. Potential mechanisms of progranulin-deficient FTLD. J Mol Neurosci. 2011 Nov;45(3):574-82. PubMed.
  2. Lee MJ, Chen TF, Cheng TW, Chiu MJ. rs5848 variant of progranulin gene is a risk of Alzheimer's disease in the Taiwanese population. Neurodegener Dis. 2011;8(4):216-20. PubMed.
  3. Yin F, Banerjee R, Thomas B, Zhou P, Qian L, Jia T, Ma X, Ma Y, Iadecola C, Beal MF, Nathan C, Ding A. Exaggerated inflammation, impaired host defense, and neuropathology in progranulin-deficient mice. J Exp Med. 2010 Jan 18;207(1):117-28. PubMed.
  4. Sleegers K, Brouwers N, Van Damme P, Engelborghs S, Gijselinck I, van der Zee J, Peeters K, Mattheijssens M, Cruts M, Vandenberghe R, De Deyn PP, Robberecht W, Van Broeckhoven C. Serum biomarker for progranulin-associated frontotemporal lobar degeneration. Ann Neurol. 2009 May;65(5):603-9. PubMed.
  5. Sleegers K, Brouwers N, Maurer-Stroh S, van Es MA, Van Damme P, van Vught PW, van der Zee J, Serneels S, De Pooter T, Van den Broeck M, Cruts M, Schymkowitz J, De Jonghe P, Rousseau F, van den Berg LH, Robberecht W, Van Broeckhoven C. Progranulin genetic variability contributes to amyotrophic lateral sclerosis. Neurology. 2008 Jul 22;71(4):253-9. PubMed.
  6. Brouwers N, Nuytemans K, van der Zee J, Gijselinck I, Engelborghs S, Theuns J, Kumar-Singh S, Pickut BA, Pals P, Dermaut B, Bogaerts V, De Pooter T, Serneels S, Van den Broeck M, Cuijt I, Mattheijssens M, Peeters K, Sciot R, Martin JJ, Cras P, Santens P, Vandenberghe R, De Deyn PP, Cruts M, Van Broeckhoven C, Sleegers K. Alzheimer and Parkinson diagnoses in progranulin null mutation carriers in an extended founder family. Arch Neurol. 2007 Oct;64(10):1436-46. PubMed.
  7. Josephs KA, Ahmed Z, Katsuse O, Parisi JF, Boeve BF, Knopman DS, Petersen RC, Davies P, Duara R, Graff-Radford NR, Uitti RJ, Rademakers R, Adamson J, Baker M, Hutton ML, Dickson DW. Neuropathologic features of frontotemporal lobar degeneration with ubiquitin-positive inclusions with progranulin gene (PGRN) mutations. J Neuropathol Exp Neurol. 2007 Feb;66(2):142-51. PubMed.
  8. van der Zee J, Le Ber I, Maurer-Stroh S, Engelborghs S, Gijselinck I, Camuzat A, Brouwers N, Vandenberghe R, Sleegers K, Hannequin D, Dermaut B, Schymkowitz J, Campion D, Santens P, Martin JJ, Lacomblez L, De Pooter T, Peeters K, Mattheijssens M, Vercelletto M, Van den Broeck M, Cruts M, De Deyn PP, Rousseau F, Brice A, Van Broeckhoven C. Mutations other than null mutations producing a pathogenic loss of progranulin in frontotemporal dementia. Hum Mutat. 2007 Apr;28(4):416. PubMed.

Primary Papers

  1. Perry DC, Lehmann M, Yokoyama JS, Karydas A, Lee JJ, Coppola G, Grinberg LT, Geschwind D, Seeley WW, Miller BL, Rosen H, Rabinovici G. Progranulin mutations as risk factors for Alzheimer disease. JAMA Neurol. 2013 Jun 1;70(6):774-8. PubMed.

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