Frontotemporal dementia as a consequence of GRN mutations: From disease cause to models to therapies

Topic: Brain proteins, microglia and lab models

Frontotemporal dementia (FTD) encompasses a broad, clinically and neuropathologically diverse group of neurodegenerative disorders associated with changes in personality, behaviour, and/or language due to the progressive degeneration of the frontal and temporal lobes of the brain. Mutations in several genes, including the progranulin (PGRN) encoding gene (GRN), have been found to cause FTD. PGRN is a pleiotropic factor with an important role in controlling lysosomal homeostasis, inflammatory processes, and neural function and differentiation under normal and pathological conditions. Heterozygosity for disease-causing, loss-of-function mutations in GRN reduces circulating PGRN levels, suggesting that familial FTD is related to PGRN haploinsufficiency. Since the original identification of FTD-causative mutations in the GRN gene in 2006, significant progress in both preclinical and clinical research has resulted in improved disease understanding of GRN-FTD, which have facilitated the development of several promising therapeutic approaches currently in preclinical testing and early and late stage clinical trials.

@article{salzano2025-40972833,
  author  = {Salzano, Sara and Bertasini, Chiara and Haghighi, Shima Tavakolian and Lundkvist, Johan and Wahlberg, Lars U. and Chiamulera, Cristiano and Vattemi, Gaetano Nicola Alfio and Gardoni, Fabrizio and others},
  title   = {{Frontotemporal dementia as a consequence of GRN mutations: From disease cause to models to therapies}},
  journal = {Pharmacological Research},
  year    = {2025},
  doi     = {10.1016/j.phrs.2025.107957},
  pmid    = {40972833},
  url     = {https://doi.org/10.1016/j.phrs.2025.107957}
}

Key findings

• Frontotemporal dementia (FTD) encompasses a broad, clinically and neuropathologically diverse group of neurodegenerative disorders associated with changes in personality, behaviour, and/or language due to the progressive degeneration of the frontal and temporal lobes of the brain.
• Heterozygosity for disease-causing, loss-of-function mutations in GRN reduces circulating PGRN levels, suggesting that familial FTD is related to PGRN haploinsufficiency.
• Since the original identification of FTD-causative mutations in the GRN gene in 2006, significant progress in both preclinical and clinical research has resulted in improved disease understanding of GRN-FTD, which have facilitated the development of several promising therapeutic approaches currently in preclinical testing and early and late stage clinical trials.

Why it matters

This review describes how loss-of-function mutations in the GRN gene reduce levels of progranulin and cause familial frontotemporal dementia, and notes that several therapeutic approaches are in preclinical testing and clinical trials. It summarizes progress toward potential therapies but does not report a proven treatment or cure.

Study details

• Evidence strengthLow

Read the original

• DOI: 10.1016/j.phrs.2025.107957
• PubMed: 40972833
• Original source →
• Free full text: Pharmacological Research →

Full text: free to read — OpenAlex lists this copy as free to read: the link above (checked 6 Feb 1020).

Studies this one cites

Referenced by this study and also in the alzhub library, so you can read them here. Showing 12 of 30.

• Progranulin AAV gene therapy for frontotemporal dementia: translational studies and phase 1/2 trial interim results Nature medicine · 2024-05-14 · usefulness score 71/100 · Long-term cohort studies
• The heritability and genetics of frontotemporal lobar degeneration Neurology · 2009-11-01 · usefulness score 65/100 · Getting a diagnosis
• Null mutations in progranulin cause ubiquitin-positive frontotemporal dementia linked to chromosome 17q21 Nature · 2006-07-16 · usefulness score 64/100 · Lewy body dementia
• Divergent network connectivity changes in behavioural variant frontotemporal dementia and Alzheimer's disease Brain : a journal of neurology · 2010-04-21 · usefulness score 64/100 · Getting a diagnosis
• Serum neurofilament light chain protein is a measure of disease intensity in frontotemporal dementia Neurology · 2016-08-31 · usefulness score 63/100 · Lewy body dementia
• Ubiquitinated TDP-43 in frontotemporal lobar degeneration and amyotrophic lateral sclerosis Science (New York, N.Y.) · 2006-10-01 · usefulness score 62/100 · Lewy body dementia
• Presymptomatic cognitive and neuroanatomical changes in genetic frontotemporal dementia in the Genetic Frontotemporal dementia Initiative (GENFI) study: a cross-sectional analysis The Lancet. Neurology · 2015-02-04 · usefulness score 62/100 · Lewy body dementia
• Mutations in progranulin cause tau-negative frontotemporal dementia linked to chromosome 17 Nature · 2006-07-16 · usefulness score 61/100 · Lewy body dementia
• Plasma progranulin levels predict progranulin mutation status in frontotemporal dementia patients and asymptomatic family members Brain : a journal of neurology · 2009-01-21 · usefulness score 60/100 · Lewy body dementia
• The evolution and pathology of frontotemporal dementia Brain : a journal of neurology · 2005-07-20 · usefulness score 59/100 · How common it is
• Mutations in progranulin are a major cause of ubiquitin-positive frontotemporal lobar degeneration Human molecular genetics · 2006-09-01 · usefulness score 59/100 · Lewy body dementia
• Plasma glial fibrillary acidic protein is raised in progranulin-associated frontotemporal dementia Journal of neurology, neurosurgery, and psychiatry · 2020-01-14 · usefulness score 57/100 · Cognitive tests and assessment

Related studies in Lewy body dementia

• Missense and silent tau gene mutations cause frontotemporal dementia with parkinsonism-chromosome 17 type, by affecting multiple alternative RNA splicing regulatory elements Proceedings of the National Academy of Sciences of the United States of America · 1999-05-01 · usefulness score 51/100
• White matter hyperintensities precede other biomarkers in GRN frontotemporal dementia Alzheimer s & Dementia · 2025-10-01 · usefulness score 48/100
• Mutations in UBQLN2 cause dominant X-linked juvenile and adult-onset ALS and ALS/dementia Nature · 2011-08-21 · usefulness score 62/100
• Cloning of the gene containing mutations that cause PARK8-linked Parkinson's disease Neuron · 2004-11-01 · usefulness score 58/100
• Mutations in the Matrin 3 gene cause familial amyotrophic lateral sclerosis Nature neuroscience · 2014-03-30 · usefulness score 58/100
• Mutations in LRRK2 cause autosomal-dominant parkinsonism with pleomorphic pathology Neuron · 2004-11-01 · usefulness score 57/100

Also tagged “bodies”

1,017 studies in the library carry the topic tag “bodies”; these are this study's neighbours in a fixed, alphabetical-by-hash tour of them, not the closest in content. All 1,017 tagged studies.

• Cognitive impairments in Parkinson's disease Neurologic clinics · 1992-05-01 · usefulness score 39/100 · Digital health tools
• Default network is not hypoactive in dementia with fluctuating cognition: an Alzheimer disease/dementia with Lewy bodies comparison Neurobiology of aging · 2012-10-11 · usefulness score 42/100 · Brain scans and imaging
• The limbic and neocortical contribution of α-synuclein, tau, and amyloid β to disease duration in dementia with Lewy bodies Alzheimer's & dementia : the journal of the Alzheimer's Association · 2017-10-31 · usefulness score 53/100 · Digital health tools

Similar studies

• Recent advances in the genetics of frontotemporal dementia 2019 · TREM2 and immune genetics
• An update on genetic frontotemporal dementia 2019 · Prevention and risk
• Parkinsonism, movement disorders and genetics in frontotemporal dementia 2016 · TREM2 and immune genetics
• Defining the spectrum of frontotemporal dementias associated with TARDBP mutations 2016 · Disparities
• Rates of Brain Atrophy Across Disease Stages in Familial Frontotemporal Dementia Associated With MAPT, GRN, and C9orf72 Pathogenic Variants 2020 · Long-term cohort studies
• Advances in understanding the molecular basis of frontotemporal dementia 2012 · Disparities

More on Lewy body dementia

• A review that covers this ground Invited review: Frontotemporal dementia caused by microtubule-associated protein tau gene (MAPT) mutations: a chameleon for neuropathology and neuroimaging Neuropathology and applied neurobiology · 2015-02-01 · usefulness score 62/100
• Newest in this subject Frequency-Resolved Connectivity Graphs for EEG-Based Classification of Alzheimer and Frontotemporal Dementia bioRxiv · 2026-10-22 · Preprint — not yet peer-reviewed · usefulness score 16/100
• Newest in this subject Dementia and PDE5 inhibitors: A retrospective cohort study of veterans Research Square · 2026-10-13 · Preprint — not yet peer-reviewed · usefulness score 16/100

See all studies in Lewy body dementia →