ArticleActa neuropathologica2019
Rare variants in the neuronal ceroid lipofuscinosis gene MFSD8 are candidate risk factors for frontotemporal dementia.
Article in Acta neuropathologica, 2019. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 27 papers.
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27 citing papers in PubMed, 39 citations in OpenAlex.
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- Integrative Genomic and Functional Analyses Reveal NINL as a Modulator of Tau Aggregation.bioRxiv : the preprint server for biology · 2025Article
- The lysosome and proteostatic stress at the intersection of pediatric neurological disorders and adult neurodegenerative diseases.Progress in neurobiology · 2025Review
- CLN7 protein functions at the interface between endolysosomes and stress granules to promote cell survival.Cell death & disease · 2025Article
- Unifying biology of neurodegeneration in lysosomal storage diseases.Journal of inherited metabolic disease · 2025Review
- Lysosome quality control in health and neurodegenerative diseases.Cellular & molecular biology letters · 2024Review
- Dem-Aging: autophagy-related pathologies and the "two faces of dementia".Neurogenetics · 2024Article
- Validation of newly derived polygenic risk scores for dementia in a prospective study of older individuals.Alzheimer's & dementia : the journal of the Alzheimer's Association · 2023Article
- Frontotemporal dementia presentation in patients with heterozygous p.H157Y variant ofJournal of medical genetics · 2023Article
- Converging links between adult-onset neurodegenerative Alzheimer's disease and early life neurodegenerative neuronal ceroid lipofuscinosis?Neural regeneration research · 2023Review
- Article
- The Drug HJournal of fungi (Basel, Switzerland) · 2022Article
- Neuroinflammation in Gaucher disease, neuronal ceroid lipofuscinosis, and commonalities with Parkinson's disease.Brain research · 2022Review
- Calmodulin binding proteins and neuroinflammation in multiple neurodegenerative diseases.BMC neuroscience · 2022Review
- Autophagy in the Neuronal Ceroid Lipofuscinoses (Batten Disease).Frontiers in cell and developmental biology · 2022Review
- Neuronal Ceroid Lipofuscinosis: The Multifaceted Approach to the Clinical Issues, an Overview.Frontiers in neurology · 2022Review
- Lysosome dysfunction as a cause of neurodegenerative diseases: Lessons from frontotemporal dementia and amyotrophic lateral sclerosis.Neurobiology of disease · 2021Review
- A lysosomal enigma CLN5 and its significance in understanding neuronal ceroid lipofuscinosis.Cellular and molecular life sciences : CMLS · 2021Review
- Review
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25 authors at 7 institutions in 1 country.
Funding
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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