Acta Neuropathologica

, Volume 137, Issue 1, pp 71–88 | Cite as

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
  • Bruce L. Miller
  • Giovanni Coppola
  • Suzee E. Lee
  • Ana Maria Cuervo
  • Jennifer S. YokoyamaEmail author
Original Paper


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.


Autophagy Frontotemporal dementia Genetics Lysosomes Neurodegeneration Neuronal ceroid lipofuscinosis 



We thank Jason Chen and the New York Genome Center for technical support of whole genome sequencing. Primary support for this study was provided by the Rainwater Charitable Foundation (JSY, AMC, SEL, GC, WWS, YH). Additional support was provided by the Bluefield Project to Cure FTD (JSY, WWS), Association for Frontotemporal Degeneration Susan Marcus Memorial Fund Clinical Research Grant (JSY), Larry L. Hillblom Foundation 2016-A-005-SUP (JSY), National Institute on Aging K01 AG049152 (JSY), John Douglas French Alzheimer’s Foundation (JSY, GC), National Institute on Aging P01 AG1972403 (BLM), National Institute on Aging P50 AG023501 (BLM), National Institute on Aging R01 AG023501, AG048030, NS079725 (YH), and R01 AG054108 (AMC), National Institutes of Health F32 AG050404 (DWS), RC1 AG035610 (GC), and R01 AG26938 (GC). Takeda Pharmaceutical Company Limited (GC). We acknowledge the support of the National Institute of Neurological Disorders and Stroke Informatics Center for Neurogenetics and Neurogenomics, P30 NS062691 (GC). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Author contributions

Experimental design: EGG, NS, SEL, AMC, JSY. Data collection: EGG, NS, MB, JNC, DWS, JHH, EMR, AD, VVB, DD, SS. Data analysis and interpretation: EGG, NS, MB, JNC, DWS, JHH, LWB, EMR, SPR, SS, LTG, WWS, BLM, GC, SEL, AMC, JSY. Subject recruitment: AK, LTG, WWS, BLM. Provided technical and/or administrative support: ANL, AK, MEB, YH, RMM. Writing the manuscript: EGG, NS, MB, AMC, JSY.

Compliance with ethical standards

Conflict of interest

YH is a co-founder and SAB member of E-Scape Bio, Inc. AMC is a co-founder and SAB member of Selphagy Inc.

Supplementary material

401_2018_1925_MOESM1_ESM.docx (10 mb)
Supplementary material 1 (DOCX 10242 kb)


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Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2018

Authors and Affiliations

  • Ethan G. Geier
    • 1
  • Mathieu Bourdenx
    • 2
  • Nadia J. Storm
    • 2
  • J. Nicholas Cochran
    • 3
  • Daniel W. Sirkis
    • 4
  • Ji-Hye Hwang
    • 1
    • 6
  • Luke W. Bonham
    • 1
  • Eliana Marisa Ramos
    • 8
  • Antonio Diaz
    • 2
  • Victoria Van Berlo
    • 8
  • Deepika Dokuru
    • 8
  • Alissa L. Nana
    • 1
  • Anna Karydas
    • 1
  • Maureen E. Balestra
    • 5
  • Yadong Huang
    • 5
    • 6
    • 7
  • Silvia P. Russo
    • 1
  • Salvatore Spina
    • 1
    • 6
  • Lea T. Grinberg
    • 1
    • 6
  • William W. Seeley
    • 1
    • 6
  • Richard M. Myers
    • 3
  • Bruce L. Miller
    • 1
  • Giovanni Coppola
    • 8
  • Suzee E. Lee
    • 1
  • Ana Maria Cuervo
    • 2
  • Jennifer S. Yokoyama
    • 1
    Email author
  1. 1.Department of Neurology, Memory and Aging CenterUniversity of California, San FranciscoSan FranciscoUSA
  2. 2.Department of Development and Molecular Biology, Institute for Aging StudiesAlbert Einstein College of MedicineNew YorkUSA
  3. 3.HudsonAlpha Institute for BiotechnologyHuntsvilleUSA
  4. 4.Department of Molecular and Cell Biology, Howard Hughes Medical InstituteUniversity of California, BerkeleyBerkeleyUSA
  5. 5.Gladstone Institute of Neurological DiseaseSan FranciscoUSA
  6. 6.Department of PathologyUniversity of California, San FranciscoSan FranciscoUSA
  7. 7.Department of NeurologyUniversity of California, San FranciscoSan FranciscoUSA
  8. 8.Department of Psychiatry and Semel Institute for Neuroscience and Human Behavior, The David Geffen School of MedicineUniversity of California, Los AngelesLos AngelesUSA

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