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MRC Prion Unit
From fundamental research to prevention and cure

Molecular basis of frontotemporal dementia and motor neuron disease

My group studies the molecular basis of two related neurodegenerative diseases: frontotemporal dementia (FTD) and motor neuron disease (MND). FTD is a common form of young-onset dementia and is characterised by changes in personality and language. MND is characterised by progressive weakness and paralysis. FTD and MND can be caused by mutations in the same gene, and can co-occur in the same individual. Therefore, FTD and MND are now considered overlapping clinical syndromes with common causes.  

Our approach is to generate cellular and animal models of genetically inherited forms of FTD and MND, in parallel with analysis of patient iPSC-neurons and brain tissue, in order to elucidate the mechanisms that lead to neuronal dysfunction and death. We are also developing drug screens based on this knowledge to identify potential therapeutics. Our main focus is on two disease genes, CHMP2B and C9orf72.

CHMP2B causes frontotemporal dementia linked to chromosome 3, a rare form of FTD that occurs in a large Danish family. CHMP2B is part of ESCRT-III (endosomal sorting complex required for transport-III), a multi-protein complex required for degradation events in the autophagy and endosome-lysosome pathways. We have shown that mutant CHMPB affects degradation in both of these pathways and are interested in how defects in these essential lysosomal degradation pathways specifically lead to impaired neuronal function. To address this question we are using a range of imaging and proteomic approaches in our collection of models and patient tissue. We are also testing therapeutic approaches that can alleviate endo-lysosome dysfunction in these models.

An expanded GGGGCC repeat in a non-coding region of the C9orf72 gene is the most common known cause of both FTD and MND. We have shown that the expanded repeats form nuclear RNA aggregates in patient brain, which may cause toxicity by sequestering RNA-binding proteins. Remarkably, the expanded repeats can initiate their own translation via a phenomenon termed repeat associated non-ATG (RAN) translation. RAN proteins also aggregate in patient brain and we have shown that they can be potently neurotoxic in vivo. We are currently investigating both RNA and RAN protein mechanisms of neurodegeneration using a range of model systems including Drosophila and patient iPSC-neurons, We have also shown, using biophysical methods, that the GGGGCC repeat RNA forms a structure termed a G-quadruplex. We are now collaborating with the UCL School of Pharmacy to develop G-quadruplex-binding small molecules as potential therapeutics.

Recent publications :

Gami, P., Murray, C., Schottlaender, L., Bettencourt, C., de Pablo Fernandez, E., Mudanohwo, E., . . . Lashley, T. (2015). A 30-unit hexanucleotide repeat expansion in C9orf72 induces pathological lesions with dipeptide-repeat proteins and RNA foci, but not TDP-43 inclusions and clinical disease. Acta Neuropathologica. doi:10.1007/s00401-015-1473-5

Rohrer, J. D., Isaacs, A. M., Mizlienska, S., Mead, S., Lashley, T., Wray, S., . . . Warren, J. D. (2015). C9orf72 expansions in frontotemporal dementia and amyotrophic lateral sclerosis. The Lancet Neurology, 14 (3), 291-301. doi:10.1016/S1474-4422(14)70233-9

Falcon, B., Cavallini, A., Angers, R., Glover, S., Murray, T. K., Barnham, L., . . . Bose, S. (2015). Conformation determines the seeding potencies of native and recombinant Tau aggregates. J Biol Chem, 290 (2), 1049-1065. doi:10.1074/jbc.M114.589309

Clayton, E. L., Mizielinska, S., Edgar, J. R., Nielsen, T. T., Marshall, S., Norona, F. E., . . . Isaacs, A. M. (2015). Frontotemporal dementia caused by CHMP2B mutation is characterised by neuronal lysosomal storage pathology. Acta Neuropathologica. doi:10.1007/s00401-015-1475-3

Simone, R., Fratta, P., Isaacs, A. M., Neidle, S., & Parkinson, G. N. (2015). G-quadruplexes: Emerging roles in neurodegenerative diseases and the non-coding transcriptome. FEBS Letters. doi:10.1016/j.febslet.2015.05.003

Chassefeyre, R., Martinez-Hernandez, J., Bertaso, F., Bouquier, N., Blot, B., Laporte, M., . . . Goldberg, Y. (2015). Regulation of Postsynaptic Function by the Dementia-Related ESCRT-III Subunit CHMP2B. JOURNAL OF NEUROSCIENCE, 35 (7), 3155-3173. doi:10.1523/JNEUROSCI.0586-14.2015

Fratta, P., Polke, J. M., Newcombe, J., Mizielinska, S., Lashley, T., Poulter, M., . . . Fisher, E. M. (2015). Screening a UK amyotrophic lateral sclerosis cohort provides evidence of multiple origins of the C9orf72 expansion. Neurobiol Aging, 36 (1), 546.e1-546.e7. doi:10.1016/j.neurobiolaging.2014.07.037

Bit-Ivan, E. N., Lee, K. -. H., Gitelman, D., Weintraub, S., Mesulam, M., Rademakers, R., . . . Bigio, E. H. (2014). Adult polyglucosan body disease with GBE1 haploinsufficiency and concomitant frontotemporal lobar degeneration. NEUROPATHOLOGY AND APPLIED NEUROBIOLOGY, 40 (6), 778-782. doi:10.1111/nan.12144

Mizielinska, S., & Isaacs, A. M. (2014). C9orf72 amyotrophic lateral sclerosis and frontotemporal dementia: gain or loss of function?. Curr Opin Neurol, 27 (5), 515-523. doi:10.1097/WCO.0000000000000130

Mizielinska, S., Grönke, S., Niccoli, T., Ridler, C. E., Clayton, E. L., Devoy, A., . . . Isaacs, A. M. (2014). C9orf72 repeat expansions cause neurodegeneration in Drosophila through arginine-rich proteins. Science. doi:10.1126/science.1256800

Mizielinska, S., Lashley, T., Norona, F. E., Clayton, E. L., Ridler, C. E., Fratta, P., & Isaacs, A. M. (2013). C9orf72 frontotemporal lobar degeneration is characterised by frequent neuronal sense and antisense RNA foci. Acta Neuropathol, 126 (6), 845-857. doi:10.1007/s00401-013-1200-z

Lashley, T., Rohrer, J. D., Mahoney, C. J., Polke, J. M., Ryan, N. S., Isaacs, A., . . . Revesz, T. (2013). Clinical and pathological features of frontotemporal dementia linked to C9ORF72 homozygosity. NEUROPATHOLOGY AND APPLIED NEUROBIOLOGY, 39, 30-31.

Stokholm, J., Teasdale, T. W., Johannsen, P., Nielsen, J. E., Nielsen, T. T., Isaacs, A., . . . Frontotemporal dementia Research in Jutland Association (FReJA) consortium. (2013). Cognitive impairment in the preclinical stage of dementia in FTD-3 CHMP2B mutation carriers: a longitudinal prospective study. J Neurol Neurosurg Psychiatry, 84 (2), 170-176. doi:10.1136/jnnp-2012-303813

Fratta, P., Poulter, M., Lashley, T., Rohrer, J. D., Polke, J. M., Beck, J., . . . Mead, S. (2013). Homozygosity for the C9orf72 GGGGCC repeat expansion in frontotemporal dementia. Acta Neuropathol, 126 (3), 401-409. doi:10.1007/s00401-013-1147-0

Beck, J., Poulter, M., Hensman, D., Rohrer, J. D., Mahoney, C. J., Adamson, G., . . . Mead, S. (2013). Large C9orf72 hexanucleotide repeat expansions are seen in multiple neurodegenerative syndromes and are more frequent than expected in the UK population. Am J Hum Genet, 92 (3), 345-353. doi:10.1016/j.ajhg.2013.01.011

Lashley, T., Hardy, J., & Isaacs, A. M. (2013). RANTing about C9orf72. Neuron, 77 (4), 597-598. doi:10.1016/j.neuron.2013.02.009

Fratta, P., Mizielinska, S., Nicoll, A. J., Zloh, M., Fisher, E. M., Parkinson, G., & Isaacs, A. M. (2012). C9orf72 hexanucleotide repeat associated with amyotrophic lateral sclerosis and frontotemporal dementia forms RNA G-quadruplexes. Sci Rep, 2, 1016-?. doi:10.1038/srep01016

Mead, S., Beck, J., Poulter, M., Rohrer, J., Adamson, G., Hensman, D., . . . Collinge, J. (2012). Large C9ORF72 hexanucleotide expansions arise spontaneously in the healthy population but can be distinguished from pathogenic mutations by Sothern Blotting. DEMENTIA AND GERIATRIC COGNITIVE DISORDERS, 33, 285-286.

Lunau, L., Mourisdsen, K., Rodell, A., Ostergaard, L., Nielsen, J. E., Isaacs, A., . . . The FReJA Consortium. (2012). Presymptomatic cerebral blood flow changes in CHMP2B mutation carriers of familial frontotemporal dementia (FTD-3), measured with MRI. BMJ: British Medical Journal.

Ghazi-Noori, S., Froud, K. E., Mizielinska, S., Powell, C., Smidak, M., Fernandez de Marco, M., . . . Isaacs, A. M. (2012). Progressive neuronal inclusion formation and axonal degeneration in CHMP2B mutant transgenic mice. Brain, 135 (Pt 3), 819-832. doi:10.1093/brain/aws006

Nielsen, T. T., Hasholt, L., Isaacs, A. M., & Nielsen, J. E. (2012). Reversal of Pathology in CHMP2B-Mediated Frontotemporal Dementia Patient Cells Using Gene Therapy. MOLECULAR THERAPY, 20, S67.

Tolstrup Nielsen, T., Mizielinska, S., Hasholt, L., Isaacs, A., Nielsen, J., & the FReJA Consortium. (2012). Reversal of pathology in CHMP2B-mediated frontotemporal dementia patient cells using RNA interference. J Gene Med., 14(8):521-529. doi: 10.1002/jgm.2649..

Lashley, T., Rohrer, J. D., Bandopadhyay, R., Fry, C., Ahmed, Z., Isaacs, A. M., . . . Revesz, T. (2011). A comparative clinical, pathological, biochemical and genetic study of fused in sarcoma proteinopathies. Brain, 134 (Pt 9), 2548-2564. doi:10.1093/brain/awr160

Rohrer, J. D., Warren, J. D., Reiman, D., Uphill, J., Beck, J., Collinge, J., . . . Mead, S. (2011). A novel exon 2 I27V VCP variant is associated with dissimilar clinical syndromes. J Neurol, 258 (8), 1494-1496. doi:10.1007/s00415-011-5966-4

FISHER, E., Johannsen, P., Fraham-Falkenberg, S., Law, I., Jennum, P., Isaacs, A., . . . Nielsen, J. E. (n.d.). Changes in cerebral glucose metabolism in early symptomatic frontotemporal dementia linked to chromosome 3 (FTD-3).


Rohrer, J. D., Lashley, T., Schott, J. M., Warren, J. E., Mead, S., Isaacs, A. M., . . . Warren, J. D. (2011). Clinical and neuroanatomical signatures of tissue pathology in frontotemporal lobar degeneration. Brain, 134 (9), 2565-2581.

Isaacs, A. M., Johannsen, P., Holm, I., Nielsen, J. E., & FReJA consortium. (2011). Frontotemporal dementia caused by CHMP2B mutations. Curr Alzheimer Res, 8 (3), 246-251.

Mackenzie, I. R., Neumann, M., Cairns, N. J., Munoz, D. G., & Isaacs, A. M. (2011). Novel types of frontotemporal lobar degeneration: beyond tau and TDP-43. J Mol Neurosci, 45 (3), 402-408. doi:10.1007/s12031-011-9551-1

Rohrer, J. D., Lashley, T., Holton, J., Revesz, T., Urwin, H., Isaacs, A. M., . . . Warren, J. (2011). The clinical and neuroanatomical phenotype of FUS associated frontotemporal lobar degeneration. J Neurol Neurosurg Psychiatry, 82 (12), 1405-1407. doi:10.1136/jnnp.2010.214437

Urwin, H., Authier, A., Nielsen, J. E., Metcalf, D., Powell, C., Froud, K., . . . Isaacs, A. M. (2010). Disruption of endocytic trafficking in frontotemporal dementia with CHMP2B mutations. Hum Mol Genet, 19 (11), 2228-2238. doi:10.1093/hmg/ddq100

Urwin, H., Josephs, K. A., Rohrer, J. D., Mackenzie, I. R., Neumann, M., Authier, A., . . . Isaacs, A. M. (2010). FUS pathology defines the majority of tau- and TDP-43-negative frontotemporal lobar degeneration. Acta Neuropathol, 120 (1), 33-41. doi:10.1007/s00401-010-0698-6

Metcalf, D., & Isaacs, A. M. (2010). The role of ESCRT proteins in fusion events involving lysosomes, endosomes and autophagosomes. Biochem Soc Trans, 38 (6), 1469-1473. doi:10.1042/BST0381469

Loy, C. T., McCusker, E., Kril, J. J., Kwok, J. B., Brooks, W. S., McCann, H., . . . Halliday, G. M. (2010). Very early-onset frontotemporal dementia with no family history predicts underlying fused in sarcoma pathology. Brain, 133 (Pt 12), e158-?. doi:10.1093/brain/awq186

Holm, I. E., Isaacs, A. M., & Mackenzie, I. R. (2009). Absence of FUS-immunoreactive pathology in frontotemporal dementia linked to chromosome 3 (FTD-3) caused by mutation in the CHMP2B gene. Acta Neuropathol, 118 (5), 719-720.

Eskildsen, S. F., Ostergaard, L. R., Rodell, A. B., Ostergaard, L., Nielsen, J. E., Isaacs, A. M., & Johannsen, P. (2009). Cortical volumes and atrophy rates in FTD-3 CHMP2B mutation carriers and related non-carriers. NeuroImage, 45 (3), 713-721.

Rohrer, J. D., Ahsan, R. L., Isaacs, A. M., Nielsen, J. E., Ostergaard, L., Scahill, R., . . . Johannsen, P. (2009). Presymptomatic generalized brain atrophy in frontotemporal dementia caused by CHMP2B mutation. Dementia and Geriatric Cognitive Disorders, 27 (2), 182-186. doi:10.1159/000200466

Rohrer, J. D., Guerreiro, R., Vandrovcova, J., Uphill, J., Reiman, D., Beck, J., . . . Rossor, M. N. (2009). The heritability and genetics of frontotemporal lobar degeneration. Neurology, 73 (18), 1451-1456. doi:10.1212/WNL.0b013e3181bf997a

Urwin, H., Ghazi-Noori, S., Collinge, J., & Isaacs, A. (2009). The role of CHMP2B in frontotemporal dementia. Biochemical Society Transactions, 37 (1), 208-212. doi:10.1042/BST0370208

Beck, J., Rohrer, J. D., Campbell, T., Isaacs, A., Morrison, K. E., Goodall, E. F., . . . Mead, S. (2008). A distinct clinical, neuropsychological and radiological phenotype is associated with progranulin gene mutations in a large UK series. Brain, 131 (3), 706-720. doi:10.1093/brain/awm320

Gromley, K. M., Rankin, J., Hilton, D. A., Isaacs, A., Mackenzie, I. R. A., & Gutowski, N. J. (2008). A novel frontotemporal dementia with pre-existing cognitive and motor impairment. JOURNAL OF NEUROLOGY NEUROSURGERY AND PSYCHIATRY, 79 (3), 353. B M J PUBLISHING GROUP.

Johannsen, P., Eskildsen, S. F., Nielsen, J. E., Isaacs, A., Zeidler, D., & Ostergaard, L. (2008). Accelerated cortical thinning in FTD3 CHMP2B mutation carriers. EUROPEAN JOURNAL OF NEUROLOGY, 15, 23. BLACKWELL PUBLISHING.

van der Zee, J., Urwin, H., Engelborghs, S., Bruyland, M., Vandenberghe, R., Dermaut, B., . . . Van Broeckhoven, C. (2008). CHMP2B C-truncating mutations in frontotemporal lobar degeneration are associated with an aberrant endosomal phenotype in vitro. Hum Mol Genet, 17 (2), 313-322. doi:10.1093/hmg/ddm309

Loerch, P. M., Lu, T., Dakin, K. A., Vann, J. M., Isaacs, A., Geula, C., . . . Yankner, B. A. (2008). Evolution of the aging brain transcriptome and synaptic regulation. PLoS ONE., 3 (10), e3329-?.

Lindquist, S. G., Braedgaard, H., Svenstrup, K., Isaacs, A. M., & Nielsen, J. E. (2008). Frontotemporal dementia linked to chromosome 3 (FTD-3)--current concepts and the detection of a previously unknown branch of the Danish FTD-3 family. Eur J Neurol, 15 (7), 667-670.

Isaacs, A. M., Powell, C., Webb, T. E., Linehan, J. M., Collinge, J., & Brandner, S. (2008). Lack of TAR-DNA binding protein-43 (TDP-43) pathology in human prion diseases. Neuropathology and Applied Neurobiology, 34 (4), 446-456. doi:10.1111/j.1365-2990.2008.00963.x

Banks, G. T., Kuta, A., Isaacs, A. M., & Fisher, E. M. C. (2008). TDP-43 is a culprit in human neurodegeneration, and not just an innocent bystander. Mammalian Genome, 19 (5), 299-305. doi:10.1007/s00335-008-9117-x

Holm, I. E., Englund, E., Mackenzie, I. R., Johannsen, P., & Isaacs, A. M. (2007). A reassessment of the neuropathology of frontotemporal dementia linked to chromosome 3. J Neuropathol Exp.Neurol, 66 (10), 884-891.

Filimonenko, M., Stuffers, S., Raiborg, C., Yamamoto, A., Malerod, L., Fisher, E. M. C., . . . Simonsen, A. (2007). Functional multivesicular bodies are required for autophagic clearance of protein aggregates associated with neurodegenerative disease. The Journal of Cell Biology, 179 (3), 485-500. doi:10.1083/jcb.200702115

Isaacs, A. M., Senn, D. B., Yuan, M., Shine, J. P., & Yankner, B. A. (2006). Acceleration of amyloid beta-peptide aggregation by physiological concentrations of calcium. J Biol Chem, 281 (38), 27916-27923.

Rastan, S., Hough, T., Kierman, A., Hardisty, R., Erven, A., Gray, I. C., . . . Brown, S. D. M. (2004). Towards a mutant map of the mouse –new models of neurological, behavioural, deafness, bone, renal and blood disorders. Genetica, 122 (1), 47-49.

Isaacs, A. M., Yuan, M., & Yankner, B. A. (2004). Transthyretin expression in the aging brain and modulation of A beta deposition. NEUROBIOLOGY OF AGING, 25, S575. ELSEVIER SCIENCE INC.

Isaacs, A. M., Oliver, P. L., Jones, E. L., Jeans, A., Potter, A., Hovik, B. H., . . . Davies, K. E. (2003). A mutation in Af4 is predicted to cause cerebellar ataxia and cataracts in the robotic mouse. J Neurosci., 23 (5), 1631-1637.

Isaacs, A. M., Jeans, A., Oliver, P. L., Vizor, L., Brown, S. D., Hunter, A. J., & Davies, K. E. (2002). Identification of a new Pmp22 mouse mutant and trafficking analysis of a Pmp22 allelic series suggesting that protein aggregates may be protective in Pmp22-associated peripheral neuropathy. Mol.Cell Neurosci., 21 (1), 114-125.

Nolan, P. M., Peters, J., Strivens, M., Rogers, D., Hagan, J., Spurr, N., . . . Hunter, J. (2000). A systematic, genome-wide, phenotype-driven mutagenesis programme for gene function studies in the mouse. Nat Genet, 25 (4), 440-443. doi:10.1038/78140

Pickering-Brown, S. M., Owen, F., Isaacs, A., Snowden, J., Varma, A., Neary, D., . . . Mann, D. M. (2000). Apolipoprotein E epsilon4 allele has no effect on age at onset or duration of disease in cases of frontotemporal dementia with pick- or microvacuolar-type histology. Exp.Neurol., 163 (2), 452-456.

Isaacs, A., Potter, A., Masih, M., Vizor, L., Oliver, P., Davies, K. E., . . . Hunter, A. J. (2000). Evaluation of neurological mouse mutants caused by ENU mutagenesis. EUR J NEUROSCI, 12, 171. BLACKWELL SCIENCE LTD.

Isaacs, A. M., Davies, K. E., Hunter, A. J., Nolan, P. M., Vizor, L., Peters, J., . . . Gray, I. C. (2000). Identification of two new Pmp22 mouse mutants using large-scale mutagenesis and a novel rapid mapping strategy. Human Molecular Genetics, 9 (12), 1865-1871.

Froelich, S., Houlden, H., Rizzu, P., Chakraverty, S., Baker, M., Kwon, J., . . . Heutink, P. (1999). Construction of a detailed physical and transcript map of the FTDP-17 candidate region on chromosome 17q21. Genomics, 60 (2), 129-136.

Hutton, M., Lendon, C. L., Rizzu, P., Baker, M., Froelich, S., Houlden, H., . . . Heutink, P. (1998). Association of missense and 5'-splice-site mutations in tau with the inherited dementia FTDP-17. Nature, 393 (6686), 702-705. doi:10.1038/31508

Isaacs, A., Baker, M., Wavrant-De Vrieze, F., & Hutton, M. (1998). Determination of the gene structure of human GFAP and absence of coding region mutations associated with frontotemporal dementia with parkinsonism linked to chromosome 17. Genomics, 51 (1), 152-154.

Baker, M., Kwok, J. B., Kucera, S., Crook, R., Farrer, M., Houlden, H., . . . Hutton, M. (1997). Localization of frontotemporal dementia with parkinsonism in an Australian kindred to chromosome 17q21-22. Ann Neurol, 42 (5), 794-798. doi:10.1002/ana.410420516

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