Rare variants in the neuronal ceroid lipofuscinosis gene MFSD8 are candidate risk factors for frontotemporal dementia

Ethan G. Geier, Mathieu Bourdenx, Nadia J. Storm, J. Nicholas Cochran, Daniel W. Sirkis, Ji Hye Hwang, Luke W. Bonham, Eliana Marisa Ramos, Antonio Diaz, Victoria Van Berlo, Deepika Dokuru, Alissa L. Nana, Anna Karydas, Maureen E. Balestra, Yadong Huang, Silvia P. Russo, Salvatore Spina, Lea T. Grinberg, William W. Seeley, Richard M. Myers & 5 others Bruce L. Miller, Giovanni Coppola, Suzee E. Lee, Ana Maria Cuervo, Jennifer S. Yokoyama

Research output: Contribution to journalArticle

1 Citation (Scopus)

Abstract

Pathogenic variation in MAPT, GRN, and C9ORF72 accounts for at most only half of frontotemporal lobar degeneration (FTLD) cases with a family history of neurological disease. This suggests additional variants and genes that remain to be identified as risk factors for FTLD. We conducted a case–control genetic association study comparing pathologically diagnosed FTLD patients (n = 94) to cognitively normal older adults (n = 3541), and found suggestive evidence that gene-wide aggregate rare variant burden in MFSD8 is associated with FTLD risk. Because homozygous mutations in MFSD8 cause neuronal ceroid lipofuscinosis (NCL), similar to homozygous mutations in GRN, we assessed rare variants in MFSD8 for relevance to FTLD through experimental follow-up studies. Using post-mortem tissue from middle frontal gyrus of patients with FTLD and controls, we identified increased MFSD8 protein levels in MFSD8 rare variant carriers relative to non-variant carrier patients with sporadic FTLD and healthy controls. We also observed an increase in lysosomal and autophagy-related proteins in MFSD8 rare variant carrier and sporadic FTLD patients relative to controls. Immunohistochemical analysis revealed that MFSD8 was expressed in neurons and astrocytes across subjects, without clear evidence of abnormal localization in patients. Finally, in vitro studies identified marked disruption of lysosomal function in cells from MFSD8 rare variant carriers, and identified one rare variant that significantly increased the cell surface levels of MFSD8. Considering the growing evidence for altered autophagy in the pathogenesis of neurodegenerative disorders, our findings support a role of NCL genes in FTLD risk and suggest that MFSD8-associated lysosomal dysfunction may contribute to FTLD pathology.

Original languageEnglish (US)
JournalActa Neuropathologica
DOIs
StateAccepted/In press - Jan 1 2018

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Frontotemporal Lobar Degeneration
Neuronal Ceroid-Lipofuscinoses
Frontotemporal Dementia
Genes
Mutation
Autophagy
Genetic Association Studies
Astrocytes
Neurodegenerative Diseases

Keywords

  • Autophagy
  • Frontotemporal dementia
  • Genetics
  • Lysosomes
  • Neurodegeneration
  • Neuronal ceroid lipofuscinosis

ASJC Scopus subject areas

  • Pathology and Forensic Medicine
  • Clinical Neurology
  • Cellular and Molecular Neuroscience

Cite this

Geier, E. G., Bourdenx, M., Storm, N. J., Cochran, J. N., Sirkis, D. W., Hwang, J. H., ... Yokoyama, J. S. (Accepted/In press). Rare variants in the neuronal ceroid lipofuscinosis gene MFSD8 are candidate risk factors for frontotemporal dementia. Acta Neuropathologica. https://doi.org/10.1007/s00401-018-1925-9

Rare variants in the neuronal ceroid lipofuscinosis gene MFSD8 are candidate risk factors for frontotemporal dementia. / Geier, Ethan G.; Bourdenx, Mathieu; Storm, Nadia J.; Cochran, J. Nicholas; Sirkis, Daniel W.; Hwang, Ji Hye; Bonham, Luke W.; Ramos, Eliana Marisa; Diaz, Antonio; Van Berlo, Victoria; Dokuru, Deepika; Nana, Alissa L.; Karydas, Anna; Balestra, Maureen E.; Huang, Yadong; Russo, Silvia P.; Spina, Salvatore; Grinberg, Lea T.; Seeley, William W.; Myers, Richard M.; Miller, Bruce L.; Coppola, Giovanni; Lee, Suzee E.; Cuervo, Ana Maria; Yokoyama, Jennifer S.

In: Acta Neuropathologica, 01.01.2018.

Research output: Contribution to journalArticle

Geier, EG, Bourdenx, M, Storm, NJ, Cochran, JN, Sirkis, DW, Hwang, JH, Bonham, LW, Ramos, EM, Diaz, A, Van Berlo, V, Dokuru, D, Nana, AL, Karydas, A, Balestra, ME, Huang, Y, Russo, SP, Spina, S, Grinberg, LT, Seeley, WW, Myers, RM, Miller, BL, Coppola, G, Lee, SE, Cuervo, AM & Yokoyama, JS 2018, 'Rare variants in the neuronal ceroid lipofuscinosis gene MFSD8 are candidate risk factors for frontotemporal dementia', Acta Neuropathologica. https://doi.org/10.1007/s00401-018-1925-9
Geier, Ethan G. ; Bourdenx, Mathieu ; Storm, Nadia J. ; Cochran, J. Nicholas ; Sirkis, Daniel W. ; Hwang, Ji Hye ; Bonham, Luke W. ; Ramos, Eliana Marisa ; Diaz, Antonio ; Van Berlo, Victoria ; Dokuru, Deepika ; Nana, Alissa L. ; Karydas, Anna ; Balestra, Maureen E. ; Huang, Yadong ; Russo, Silvia P. ; Spina, Salvatore ; Grinberg, Lea T. ; Seeley, William W. ; Myers, Richard M. ; Miller, Bruce L. ; Coppola, Giovanni ; Lee, Suzee E. ; Cuervo, Ana Maria ; Yokoyama, Jennifer S. / Rare variants in the neuronal ceroid lipofuscinosis gene MFSD8 are candidate risk factors for frontotemporal dementia. In: Acta Neuropathologica. 2018.
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abstract = "Pathogenic variation in MAPT, GRN, and C9ORF72 accounts for at most only half of frontotemporal lobar degeneration (FTLD) cases with a family history of neurological disease. This suggests additional variants and genes that remain to be identified as risk factors for FTLD. We conducted a case–control genetic association study comparing pathologically diagnosed FTLD patients (n = 94) to cognitively normal older adults (n = 3541), and found suggestive evidence that gene-wide aggregate rare variant burden in MFSD8 is associated with FTLD risk. Because homozygous mutations in MFSD8 cause neuronal ceroid lipofuscinosis (NCL), similar to homozygous mutations in GRN, we assessed rare variants in MFSD8 for relevance to FTLD through experimental follow-up studies. Using post-mortem tissue from middle frontal gyrus of patients with FTLD and controls, we identified increased MFSD8 protein levels in MFSD8 rare variant carriers relative to non-variant carrier patients with sporadic FTLD and healthy controls. We also observed an increase in lysosomal and autophagy-related proteins in MFSD8 rare variant carrier and sporadic FTLD patients relative to controls. Immunohistochemical analysis revealed that MFSD8 was expressed in neurons and astrocytes across subjects, without clear evidence of abnormal localization in patients. Finally, in vitro studies identified marked disruption of lysosomal function in cells from MFSD8 rare variant carriers, and identified one rare variant that significantly increased the cell surface levels of MFSD8. Considering the growing evidence for altered autophagy in the pathogenesis of neurodegenerative disorders, our findings support a role of NCL genes in FTLD risk and suggest that MFSD8-associated lysosomal dysfunction may contribute to FTLD pathology.",
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AU - Geier, Ethan G.

AU - Bourdenx, Mathieu

AU - Storm, Nadia J.

AU - Cochran, J. Nicholas

AU - Sirkis, Daniel W.

AU - Hwang, Ji Hye

AU - Bonham, Luke W.

AU - Ramos, Eliana Marisa

AU - Diaz, Antonio

AU - Van Berlo, Victoria

AU - Dokuru, Deepika

AU - Nana, Alissa L.

AU - Karydas, Anna

AU - Balestra, Maureen E.

AU - Huang, Yadong

AU - Russo, Silvia P.

AU - Spina, Salvatore

AU - Grinberg, Lea T.

AU - Seeley, William W.

AU - Myers, Richard M.

AU - Miller, Bruce L.

AU - Coppola, Giovanni

AU - Lee, Suzee E.

AU - Cuervo, Ana Maria

AU - Yokoyama, Jennifer S.

PY - 2018/1/1

Y1 - 2018/1/1

N2 - Pathogenic variation in MAPT, GRN, and C9ORF72 accounts for at most only half of frontotemporal lobar degeneration (FTLD) cases with a family history of neurological disease. This suggests additional variants and genes that remain to be identified as risk factors for FTLD. We conducted a case–control genetic association study comparing pathologically diagnosed FTLD patients (n = 94) to cognitively normal older adults (n = 3541), and found suggestive evidence that gene-wide aggregate rare variant burden in MFSD8 is associated with FTLD risk. Because homozygous mutations in MFSD8 cause neuronal ceroid lipofuscinosis (NCL), similar to homozygous mutations in GRN, we assessed rare variants in MFSD8 for relevance to FTLD through experimental follow-up studies. Using post-mortem tissue from middle frontal gyrus of patients with FTLD and controls, we identified increased MFSD8 protein levels in MFSD8 rare variant carriers relative to non-variant carrier patients with sporadic FTLD and healthy controls. We also observed an increase in lysosomal and autophagy-related proteins in MFSD8 rare variant carrier and sporadic FTLD patients relative to controls. Immunohistochemical analysis revealed that MFSD8 was expressed in neurons and astrocytes across subjects, without clear evidence of abnormal localization in patients. Finally, in vitro studies identified marked disruption of lysosomal function in cells from MFSD8 rare variant carriers, and identified one rare variant that significantly increased the cell surface levels of MFSD8. Considering the growing evidence for altered autophagy in the pathogenesis of neurodegenerative disorders, our findings support a role of NCL genes in FTLD risk and suggest that MFSD8-associated lysosomal dysfunction may contribute to FTLD pathology.

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