Granulins Rescue Inflammation, Lysosome Dysfunction, and Neuropathology in a Mouse Model of Progranulin Deficiency

Root, Jessica; Mendsaikhan, Anarmaa; Nandy, Srijita; Taylor, Georgia; Wang, Minzheng; Araujo, Ludmilla Troiano; Merino, Paola; Ryu, Danny; Holler, Christopher J.; Thompson, Bonne M.; Astarita, Giuseppe; Blain, Jean-François; Kukar, Tom

doi:10.2139/ssrn.4438570

Cited by 3 publications

(1 citation statement)

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“…Upon increased acidification of the endo-lysosomal pathway, PGRN is proteolytically processed into granulin peptides by the lysosomal protease legumain (LGMN), also known as asparagine endopeptidase (AEP), and probably by various cathepsins, including cathepsin B and L [27][28][29] . An essential role of granulins in lysosomes is suggested, since lysosomal dysfunction caused by PGRN deficiency is ameliorated by granulin peptides 30 . Despite intense research, both the lysosomal function of PGRN / granulins and the mechanistic link between PGRN deficiency and TDP-43 aggregation remain unclear.…”

Section: Mainmentioning

confidence: 99%

Enhanced legumain activity links progranulin deficiency to TDP-43 pathology in frontotemporal lobar degeneration

Robinson,

Reich,

Mühlhofer

et al. 2024

Preprint

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Loss-of-function mutations in GRN are a major cause of frontotemporal lobar degeneration (FTLD) with TDP-43-positive inclusions. Progranulin (PGRN) loss leads to lysosomal dysfunction, microglial hyperactivation, and TDP-43 deposition, yet the underlying pathomechanism remains unknown. We demonstrate that PGRN slows the maturation and limits the proteolytic activity of the lysosomal protease legumain (LGMN). Accordingly, LGMN activity is strongly elevated in Grn knockout (ko) mice, in human induced pluripotent stem cell-derived GRN ko microglia, and in FTLD-GRN patients brain. Secreted microglial LGMN is internalized by neurons, where it mediates pathological processing of TDP-43, which is prevented by selective LGMN inhibition. In contrast, AAV-mediated overexpression of LGMN in mouse brains promotes TDP-43 processing, the aggregation of phosphorylated TDP-43 and increases plasma neurofilament light chain (NfL), a marker for neuronal loss. Our findings identify LGMN as a link between PGRN haploinsufficiency and TDP-43 pathology in FTLD-GRN and suggest LGMN as a therapeutic target.

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Section: Mainmentioning

confidence: 99%

Enhanced legumain activity links progranulin deficiency to TDP-43 pathology in frontotemporal lobar degeneration

Robinson,

Reich,

Mühlhofer

et al. 2024

Preprint

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Progranulin and GPNMB: interactions in endo-lysosome function and inflammation in neurodegenerative disease

Gillett,

Wallings,

Uriarte Huarte

et al. 2023

J Neuroinflammation

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Background Alterations in progranulin (PGRN) expression are associated with multiple neurodegenerative diseases (NDs), including frontotemporal dementia (FTD), Alzheimer’s disease (AD), Parkinson’s disease (PD), and lysosomal storage disorders (LSDs). Recently, the loss of PGRN was shown to result in endo-lysosomal system dysfunction and an age-dependent increase in the expression of another protein associated with NDs, glycoprotein non-metastatic B (GPNMB). Main body It is unclear what role GPNMB plays in the context of PGRN insufficiency and how they interact and contribute to the development or progression of NDs. This review focuses on the interplay between these two critical proteins within the context of endo-lysosomal health, immune function, and inflammation in their contribution to NDs. Short conclusion PGRN and GPNMB are interrelated proteins that regulate disease-relevant processes and may have value as therapeutic targets to delay disease progression or extend therapeutic windows.

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Characterization of Progranulin Gene Mutations in Portuguese Patients with Frontotemporal Dementia

Almeida,

Tábuas-Pereira,

Baldeiras

et al. 2023

IJMS

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In Portugal, heterozygous loss-of-function mutations in the progranulin (GRN) gene account for approximately half of the genetic mediated forms of frontotemporal dementia (FTD). GRN mutations reported thus far cause FTD through a haploinsufficiency disease mechanism. Herein, we aim to unveil the GRN mutation spectrum, investigated in 257 FTD patients and 19 family members from the central/north region of Portugal using sequencing methods. Seven different pathogenic variants were identified in 46 subjects including 40 patients (16%) and 6 relatives (32%). bvFTD was the most common clinical presentation among the GRN mutation patients, who showed a global pattern of moderate-to-severe frontotemporoparietal deficits in the neuropsychological evaluation. Interestingly, two mutations were novel (p.Thr238Profs*18, p.Leu354Profs*16), and five were previously described, although three of them only in the Portuguese population, suggesting a population-specific GRN mutational spectrum. The subjects harboring a GRN mutation showed a significant reduction in serum PGRN levels, supporting the pathogenic nature of these variants. This work broadens the mutation spectrum of GRN and the identification of the underlying GRN mutations provided an accurate genetic counselling and allowed the enrolment of subjects with GRN mutations (both asymptomatic and symptomatic) in ongoing clinical trials, which is essential to test new drugs for the disease.

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Granulins Rescue Inflammation, Lysosome Dysfunction, and Neuropathology in a Mouse Model of Progranulin Deficiency

Cited by 3 publications

References 0 publications

Enhanced legumain activity links progranulin deficiency to TDP-43 pathology in frontotemporal lobar degeneration

Enhanced legumain activity links progranulin deficiency to TDP-43 pathology in frontotemporal lobar degeneration

Progranulin and GPNMB: interactions in endo-lysosome function and inflammation in neurodegenerative disease

Characterization of Progranulin Gene Mutations in Portuguese Patients with Frontotemporal Dementia

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