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

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Geier, Ethan G., Bourdenx, Mathieu, Storm, Nadia J., Cochran, J. Nicholas, Sirkis, Daniel W., Hwang, Ji-Hye, Bonham, Luke W., Ramos, Eliana Marisa +17 more·2019·Acta Neuropathologica
DOI 10.1007/s00401-018-1925-9PMC PMC6371791
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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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  • Certain disease-associated proteins have been shown to impair lysosomal acidification.

    “Moreover, certain disease-associated proteins have been shown to impair lysosomal acidification.”

    From The lysosome and proteostatic stress at the intersection of pediatric neurological disorders and adult neurodegenerative diseases (2025) · cites this paper as [60]

    The Results section (“Lysosomal malfunctioning in MFSD8 rare variant carriers”; page not available) reports reduced lysosomal protein degradation in cells carrying FTLD-associated MFSD8 variants. It does not report a measurement or finding that these variants impair lysosomal acidification; searches for acidification and lysosomal pH returned only degradation-related passages. (LLM, conf=0.83)

    Experimental — accuracy not yet measured

  • Amyloid beta accumulation in neurons in mouse models of AD results in faulty lysosomal acidification.

    “In particular, amyloid beta accumulation in neurons in mouse models of AD has been shown to result in faulty lysosomal acidification.60”

    From The lysosome and proteostatic stress at the intersection of pediatric neurological disorders and adult neurodegenerative diseases (2025) · cites this paper as [60]

    The Results section on lysosomal malfunctioning reports impaired lysosomal degradation in cells from people carrying MFSD8 variants, not faulty lysosomal acidification in neurons of Alzheimer’s mouse models. Searches for amyloid beta, Alzheimer’s mouse models, and lysosomal acidification found no passage in our copy addressing the claimed causal relationship; page numbers were not available. (LLM, conf=0.76)

    Experimental — accuracy not yet measured

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Cited by

Sorted by citations

Authors
Geier, E. G., Bourdenx, M., Storm, N. J., Cochran, J. N., Sirkis, D. W., Hwang, J.-H., Bonham, L. W., Ramos, E. M., Diaz, A., Van Berlo, V., Dokuru, D., Nana, A. L., Karydas, A., Balestra, M. E., Huang, Y., Russo, S. P., Spina, S., Grinberg, L. T., Seeley, W. W., Myers, R. M., Miller, B. L., Coppola, G., Lee, S. E., Cuervo, A. M., & Yokoyama, J. S.
Affiliations
  • University of California, San Francisco (US)
  • Albert Einstein College of Medicine (US)
  • HudsonAlpha Institute for Biotechnology (US)
  • Howard Hughes Medical Institute (US)
  • University of California, Los Angeles (US)
  • Gladstone Institutes (US)
Corresponding author
Yokoyama, Jennifer S.
ORCID
Venue
Acta Neuropathologica
Publisher
Springer Science and Business Media LLC
Published
2018-10-31
Volume
137
Issue
1
Pages
71-88
ISSN
  • 0001-6322 (ISSN-L)
  • 1432-0533
DOI
10.1007/s00401-018-1925-9
PMC
PMC6371791
OpenAlex
W2898961633
Cited by
39
References
10
Citations by year
2026: 3 · 2025: 5 · 2024: 3 · 2023: 6 · 2022: 9 · 2021: 5 · 2020: 3 · 2019: 5
FWCI
2.23
Type
journal article
Language
en
Open access
Licence
Locations
  • Acta Neuropathologica (publishedVersion)
  • PubMed (publishedVersion)
  • Europe PMC (PubMed Central) (acceptedVersion)
  • PubMed Central (acceptedVersion)
  • eScholarship (California Digital Library) (submittedVersion)
Funders
  • Bluefield Project to Cure FTD
  • Rainwater Charitable Foundation
  • Association for Frontotemporal Degeneration (Susan Marcus Memorial Fund Clinical Research Grant)
  • Larry L. Hillblom Foundation (2016-A-005-SUP)
  • National Institute on Aging (K01 AG049152, NIA P01 AG1972403, P50 AG023501, R01 AG023501, R01 AG048030, NS079725, AG054108)
  • National Institutes of Health (RC1 AG035610, R01 AG26938, AG050404)
  • Takeda Pharmaceutical Company Limited
  • National Institute of Neurological Disorders and Stroke (P30 NS062691)
  • John Douglas French Alzheimer’s Foundation
Topics
  • Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
  • Health Sciences › Medicine › Physiology › Lysosomal Storage Disorders Research
  • Health Sciences › Medicine › Neurology › Amyotrophic Lateral Sclerosis Research
Keywords
frontotemporal lobar degeneration, frontotemporal dementia, MFSD8, neuronal ceroid lipofuscinosis, rare variants, genetic risk factors, lysosomal dysfunction, autophagy, lysosomal storage disease
MeSH terms
Aged, Female, Humans, Lysosomes, Male, Middle Aged, Mutation, Neuronal Ceroid-Lipofuscinoses, Risk Factors, Pick Disease of the Brain, Membrane Transport Proteins, Intercellular Signaling Peptides and Proteins, Genetic Association Studies, Frontotemporal Lobar Degeneration, Frontotemporal Dementia

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