From the Guidelines
The progranulin gene (GRN) is a significant causative gene in frontotemporal dementia (FTD), with mutations leading to a reduction in progranulin protein and subsequent neurodegeneration, as highlighted in a 2020 study published in the journal Brain 1.
Key Points
- GRN mutations account for approximately 20% of autosomal-dominant genetic mutations in FTD, along with hexanucleotide repeat expansions near the chromosome 9 open reading frame gene (C9orf72) and microtubule-associated protein tau (MAPT) 1.
- The diagnosis of behavioural variant FTD (bvFTD) remains challenging due to the absence of molecular biomarkers and symptomatic overlap with non-degenerative primary psychiatric disorders (PPD) 1.
- Expert clinicians have developed various approaches to identify bvFTD, but there is no consensus approach, and evidence suggests a low rate of diagnostic accuracy 1.
- Genetic testing for GRN mutations is crucial for patients with a family history of FTD or early-onset dementia, as identification can guide genetic counseling for family members 1.
Management and Treatment
- Currently, there are no approved treatments specifically targeting progranulin deficiency, though standard dementia medications like cholinesterase inhibitors may provide symptomatic relief 1.
- Several promising therapeutic approaches are in development, including gene therapy to increase progranulin levels, small molecules to enhance progranulin production, and compounds targeting downstream pathological processes 1.
- Management of FTD typically focuses on symptom control and supportive care through a multidisciplinary approach 1.
From the Research
Progranulin Gene and Dementia
- The progranulin gene (GRN) has been associated with frontotemporal dementia (FTD) and other neurodegenerative diseases 2, 3, 4, 5, 6.
- Mutations in the GRN gene can cause haploinsufficiency, leading to FTD and other forms of dementia 2, 4, 5.
- Progranulin has been shown to have neurotrophic and neuro-immunomodulatory properties, and its deficiency has been linked to neurodegenerative diseases 5, 6.
Mechanism of Action
- Progranulin is a secreted glycoprotein that consists of seven and a half tandemly repeated granulin motifs 5.
- It has been shown to have anti-inflammatory effects, promote neuron survival and neurite growth, and participate in normal lysosomal function 5, 6.
- The protein may be cleaved into granulins, which display pro-inflammatory properties 2.
Therapeutic Potential
- Progranulin replacement has been proposed as a therapeutic strategy for FTD and other neurodegenerative diseases 2, 3, 5, 6.
- Gene delivery of GRN in experimental models of Alzheimer's- and Parkinson's-like diseases has been shown to inhibit phenotype progression 5.
- AAV-mediated progranulin delivery has been shown to reduce lipofuscinosis and microgliosis in Grn-/- mice, and to correct lysosomal abnormalities 3.
Clinical Relevance
- Patients with null mutations in GRN display very low plasma PGRN levels, which can be used to identify mutation carriers and monitor disease progression 2.
- The frequency of GRN mutations has been found to be 6.9% in all FTD-spectrum cases, and 21.4% in cases with a pathological diagnosis of FTLD-U 4.
- Progranulin has been highlighted as a potential anti-neurodegeneration target in dementia, and therapeutic strategies targeting PGRN are being developed 6.