Grn, also known as the granulin precursor gene, encodes progranulin (PGRN), a lysosomal and secreted protein. PGRN plays a key role in the development, survival, function, and maintenance of neurons and microglia in the mammalian brain, regulating lysosomal biogenesis, inflammation, repair, stress response, and aging [4].

GRN loss-of-function mutations have been extensively studied. Grn-/-mice exhibit a global deficiency in bis(monoacylglycero)phosphate (BMP), an endolysosomal phospholipid that interacts with PGRN in a pH-dependent manner, and also show secondary storage of glucocerebrosidase substrate glucosylsphingosine [1]. These phenotypes can be rescued by a recombinant protein PTV:PGRN, which corrects levels of BMP, glucosylsphingosine, and disease pathology in Grn-/-CNS, including microgliosis, lipofuscinosis, and neuronal damage [1]. Heterozygous mutations in GRN cause autosomal-dominant frontotemporal dementia (FTD-GRN), associated with TDP-43 inclusions, neuronal loss, axonal degeneration and gliosis [2]. Multiple studies have demonstrated variability in clinical presentation and age of onset in patients carrying a GRN loss-of-function mutation, indicating potential disease modifiers [3]. Mutations that reduce PGRN levels increase the risk for developing Alzheimer's disease, Parkinson's disease, and limbic-predominant age-related transactivation response DNA-binding protein 43 encephalopathy, and exacerbate the progression of amyotrophic lateral sclerosis (ALS) and FTD caused by the hexanucleotide repeat expansion in the C9orf72 gene [4].

In conclusion, Grn is crucial for normal brain function, especially in maintaining lysosomal function and preventing neurodegeneration. The study of Grn-/-mouse models has provided valuable insights into the pathogenesis of neurodegenerative diseases such as frontotemporal dementia, Alzheimer's disease, and Parkinson's disease, highlighting the potential of targeting Grn-related pathways for therapeutic intervention.

References:

1. Logan, Todd, Simon, Matthew J, Rana, Anil, DeVos, Sarah L, Di Paolo, Gilbert. 2021. Rescue of a lysosomal storage disorder caused by Grn loss of function with a brain penetrant progranulin biologic. In Cell, 184, 4651-4668.e25. doi:10.1016/j.cell.2021.08.002. https://pubmed.ncbi.nlm.nih.gov/34450028/

2. Gerrits, Emma, Giannini, Lucia A A, Brouwer, Nieske, van Swieten, John C, Eggen, Bart J L. 2022. Neurovascular dysfunction in GRN-associated frontotemporal dementia identified by single-nucleus RNA sequencing of human cerebral cortex. In Nature neuroscience, 25, 1034-1048. doi:10.1038/s41593-022-01124-3. https://pubmed.ncbi.nlm.nih.gov/35879464/

3. Wauters, Eline, Van Mossevelde, Sara, Van der Zee, Julie, Cruts, Marc, Van Broeckhoven, Christine. 2017. Modifiers of GRN-Associated Frontotemporal Lobar Degeneration. In Trends in molecular medicine, 23, 962-979. doi:10.1016/j.molmed.2017.08.004. https://pubmed.ncbi.nlm.nih.gov/28890134/

4. Rhinn, Herve, Tatton, Nadine, McCaughey, Stella, Kurnellas, Michael, Rosenthal, Arnon. 2022. Progranulin as a therapeutic target in neurodegenerative diseases. In Trends in pharmacological sciences, 43, 641-652. doi:10.1016/j.tips.2021.11.015. https://pubmed.ncbi.nlm.nih.gov/35039149/