Frontotemporal Dementia Patient Neurons With Progranulin Deficiency Display Protein Dyshomeostasis

Elia, Lisa P.; Herting, Bianca; Alijagic, Amela; Buselli, Christina; Wong, Leela; Morrison, Grace; Prado, Miguel A.; Paolo, Joao; Gygi, Steven P.; Finley, Dan; Finkbeiner, Steve

doi:10.1101/2023.01.18.524611

Cited by 3 publications

(1 citation statement)

References 61 publications

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“…Mutations in the microtubuleassociated protein tau (MAPT) gene, coding for the tau protein, have been detected in certain FTD cases. These mutations can upset tau's normal function and lead to abnormal protein aggregations in the brain [28]. Mutations in other genes, like progranulin (GRN) and C9orf72, are also connected with FTD, impacting the production or processing of specific proteins involved in cellular processes [29,30].…”

Section: Neurodegenerative Diseases-gene Mutationsmentioning

confidence: 99%

Mitochondrial Dynamics in Neurodegenerative Diseases: Unraveling the Role of Fusion and Fission Processes

Grel,

Woznica,

Ratajczak

et al. 2023

IJMS

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Neurodegenerative diseases (NDs) are a diverse group of disorders characterized by the progressive degeneration and death of neurons, leading to a range of neurological symptoms. Despite the heterogeneity of these conditions, a common denominator is the implication of mitochondrial dysfunction in their pathogenesis. Mitochondria play a crucial role in creating biomolecules, providing energy through adenosine triphosphate (ATP) generated by oxidative phosphorylation (OXPHOS), and producing reactive oxygen species (ROS). When they’re not functioning correctly, becoming fragmented and losing their membrane potential, they contribute to these diseases. In this review, we explore how mitochondria fuse and undergo fission, especially in the context of NDs. We discuss the genetic and protein mutations linked to these diseases and how they impact mitochondrial dynamics. We also look at the key regulatory proteins in fusion (MFN1, MFN2, and OPA1) and fission (DRP1 and FIS1), including their post-translational modifications. Furthermore, we highlight potential drugs that can influence mitochondrial dynamics. By unpacking these complex processes, we aim to direct research towards treatments that can improve life quality for people with these challenging conditions.

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Section: Neurodegenerative Diseases-gene Mutationsmentioning

confidence: 99%

Mitochondrial Dynamics in Neurodegenerative Diseases: Unraveling the Role of Fusion and Fission Processes

Grel,

Woznica,

Ratajczak

et al. 2023

IJMS

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Patient-derived Induced Pluripotent Stem Cells as a Model to Study Frontotemporal Dementia Pathologies

Infante-Tadeo,

Barber

2024

Preprint

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The neurodegenerative disorder Frontotemporal Dementia (FTD) can be caused by a repeat expansion (GGGGCC; G4C2) in C9orf72. The function of wild-type C9orf72 and the mechanism by which the C9orf72-G4C2 mutation causes FTD, however, remain unresolved. Diverse disease models including human brain samples and differentiated neurons from patient-derived induced pluripotent stem cells (iPSCs) identified some hallmarks associated with FTD, but these models have limitations, including biopsies capturing only a static snapshot of dynamic processes and differentiated neurons being labor-intensive, costly, and post-mitotic. We find that patient-derived iPSCs, without being differentiated into neurons, exhibit established FTD hallmarks, including increased lysosome pH, decreased lysosomal cathepsin activity, cytosolic TDP-43 proteinopathy, and increased nuclear TFEB. Moreover, lowering lysosome pH in FTD iPSCs mitigates TDP-43 proteinopathy, suggesting a key role for lysosome dysfunction. RNA-seq reveals dysregulated transcripts in FTD iPSCs affecting calcium signaling, cell death, synaptic function, and neuronal development. We confirm differences in protein expression for some dysregulated genes not previously linked to FTD, including CNTFR (neuronal survival), Annexin A2 (anti-apoptotic), NANOG (neuronal development), and moesin (cytoskeletal dynamics). Our findings underscore the potential of FTD iPSCs as a model for studying FTD cellular pathology and for drug screening to identify therapeutics.SIGNIFICANCE STATEMENTUnderstanding the cellular pathology of Frontotemporal Dementia linked to a GGGGCC expansion in the C9orf72 gene remains a challenge.This study shows that undifferentiated patient-derived iPSCs exhibit hallmark FTD characteristics, including lysosome dysfunction and TDP-43 proteinopathy, and identifies dysregulated genes related to neurodegeneration.These findings highlight patient-derived iPSCs as a valuable model for studying FTD pathology and for drug screening, potentially guiding future research in therapeutic development.

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Multi-modal proteomic characterization of lysosomal function and proteostasis in progranulin-deficient neurons

Hasan,

Fernandopulle,

Humble

et al. 2023

Mol Neurodegeneration

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Background Progranulin (PGRN) is a lysosomal glycoprotein implicated in various neurodegenerative diseases, including frontotemporal dementia and neuronal ceroid lipofuscinosis. Over 70 mutations discovered in the GRN gene all result in reduced expression of the PGRN protein. Genetic and functional studies point toward a regulatory role for PGRN in lysosome functions. However, the detailed molecular function of PGRN within lysosomes and the impact of PGRN deficiency on lysosomes remain unclear. Methods We developed multifaceted proteomic techniques to characterize the dynamic lysosomal biology in living human neurons and fixed mouse brain tissues. Using lysosome proximity labeling and immuno-purification of intact lysosomes, we characterized lysosome compositions and interactome in both human induced pluripotent stem cell (iPSC)-derived glutamatergic neurons (i3Neurons) and mouse brains. Using dynamic stable isotope labeling by amino acids in cell culture (dSILAC) proteomics, we measured global protein half-lives in human i3Neurons for the first time. Results Leveraging the multi-modal proteomics and live-cell imaging techniques, we comprehensively characterized how PGRN deficiency changes the molecular and functional landscape of neuronal lysosomes. We found that PGRN loss impairs the lysosome’s degradative capacity with increased levels of v-ATPase subunits on the lysosome membrane, increased hydrolases within the lysosome, altered protein regulations related to lysosomal transport, and elevated lysosomal pH. Consistent with impairments in lysosomal function, GRN-null i3Neurons and frontotemporal dementia patient-derived i3Neurons carrying GRN mutation showed pronounced alterations in protein turnover, such as cathepsins and proteins related to supramolecular polymerization and inherited neurodegenerative diseases. Conclusion This study suggested PGRN as a critical regulator of lysosomal pH and degradative capacity, which influences global proteostasis in neurons. Beyond the study of progranulin deficiency, these newly developed proteomic methods in neurons and brain tissues provided useful tools and data resources for the field to study the highly dynamic neuronal lysosome biology. Graphical Abstract

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Frontotemporal Dementia Patient Neurons With Progranulin Deficiency Display Protein Dyshomeostasis

Cited by 3 publications

References 61 publications

Mitochondrial Dynamics in Neurodegenerative Diseases: Unraveling the Role of Fusion and Fission Processes

Mitochondrial Dynamics in Neurodegenerative Diseases: Unraveling the Role of Fusion and Fission Processes

Patient-derived Induced Pluripotent Stem Cells as a Model to Study Frontotemporal Dementia Pathologies

Multi-modal proteomic characterization of lysosomal function and proteostasis in progranulin-deficient neurons

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