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. Yokoyama
Acta Neuropathol. 2018-10-31; 137(1): 71-88
DOI: 10.1007/s00401-018-1925-9

PubMed
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Geier EG(1), Bourdenx M(2), Storm NJ(2), Cochran JN(3), Sirkis DW(4), Hwang JH(1)(5), Bonham LW(1), Ramos EM(6), Diaz A(2), Van Berlo V(6), Dokuru D(6), Nana AL(1), Karydas A(1), Balestra ME(7), Huang Y(7)(5)(8), Russo SP(1), Spina )(5), Grinberg LT(1)(5), Seeley WW(1)(5), Myers RM(3), Miller BL(1), Coppola G(6), Lee SE(1), Cuervo AM(2), Yokoyama JS(9).

Author information:
(1)Department of Neurology, Memory and Aging Center, University of California,
San Francisco, 675 Nelson Rising Lane, Suite 190, San Francisco, CA, 94158, USA.
(2)Department of Development and Molecular Biology, Institute for Aging Studies,
Albert Einstein College of Medicine, New York, NY, 10461, USA.
(3)HudsonAlpha Institute for Biotechnology, Huntsville, AL, 35806, USA.
(4)Department of Molecular and Cell Biology, Howard Hughes Medical Institute,
University of California, Berkeley, Berkeley, CA, 94720, USA.
(5)Department of Pathology, University of California, San Francisco, San
Francisco, CA, 94158, USA.
(6)Department of Psychiatry and Semel Institute for Neuroscience and Human
Behavior, The David Geffen School of Medicine, University of California, Los
Angeles, Los Angeles, CA, 90095, USA.
(7)Gladstone Institute of Neurological Disease, San Francisco, CA, USA.
(8)Department of Neurology, University of California, San Francisco, San
Francisco, CA, 94158, USA.
(9)Department of Neurology, Memory and Aging Center, University of California,
San Francisco, 675 Nelson Rising Lane, Suite 190, San Francisco, CA, 94158, USA.
.

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.

 

Auteurs Bordeaux Neurocampus