Targeting Progranulin as an Immuno-Neurology Therapeutic Approach
Abstract
:1. Introduction
2. Neuroimmunology in Dementia and Neurodegeneration
2.1. Microglial Role in Brain Function
2.2. Alterations in Microglia Function in the Context of Neurodegeneration
2.3. PGRN—A Key Neurotrophic Factor and Regulator in CNS Homeostasis and Immunity
2.4. PGRN’s Role in Human Disease
2.5. PGRN Modulation in Animal Models of Neurodegeneration
PGRN Insufficiency in FTD-GRN | PGRN Knockout in FTD-GRN Animal Models/ In Vitro | Administration of PGRN in FTD-GRN Animal Models/ In Vitro | PGRN Knockout in Animal Models of AD/In Vitro | Administration of PGRN in AD Animal Models/In Vitro | |
---|---|---|---|---|---|
Neurons | Neuronal loss; downregulation of synaptic genes; overlap with TDP-43 target RNAs [168]; cytoplasmic TDP-43 deposition [142,168,169]; tau accumulation [170] | Susceptible to apoptosis/neuronal loss [47,171,172,173,174]; hyperexcitability [175]; reduced dendritic length and reduced spine density [176]; reduction in primary neuron survival and neurite outgrowth [48,115]; lysosomal dysfunction [127,149,155,177,178]; lipofuscinosis [127,172]; results in hyperphosphorylated TDP-43/TDP-43 accumulation [119,127,142,148,155,171,178,179]; disruption of autophagy–lysosomal system [155,171]; CTSD accumulation [142] | Promotes neuronal survival and enhances neurite outgrowth in cultured neurons [50]; rescues neurons from cell death/degeneration [46,115,159,174,179]; protects cortical and motor neurons from toxin- or ischemic-mediated cell death [116]; functions as neurotrophic factor [47,48,144,177,180,181,182]; reverses social dominance deficits and corrects lysosomal dysfunction [157]; rescues TDP-43 LOF [119]; safeguards against pathological TDP-43–induced axonopathy [144]; protects against TDP-43–induced neurodegeneration [46]; reduces TDP-43 phosphorylation [174,179]; accelerates axonal regrowth [156]; stimulates phosphorylation of glycogen synthase kinase-3 beta (GSK-3β) [47] | Increases tau pathology and complement activation [161] | Protective against neuronal loss [72]; reduces synaptic loss [163] |
Microglia | Microgliosis [168,169], upregulation of C1q, complement protein; myelin debris accumulation [168]; Myelin loss and white matter pathology [169] | Hyper-inflammatory phenotype [56,148,156,171,172,173,174,178,183]; impairs phagocytosis and motility [72,175]; increases synaptic pruning [56]; lysosomal dysfunction [53,56,149,174,178]; disruption of autophagy–lysosomal system and lipofuscinosis [171]; induces aggregation of TDP-43 in adjacent neurons [57]; increases lysosomal protein and gene expression (LAMP1 and CTSDmat) [142] | Reduces microgliosis [141,179]; suppresses CTSDmat [142]; rescued oxidative stress, lysosomal dysfunction, microgliosis, and endomembrane damage [159]; increases number of microglial processes, indicating reduced activation [179] | Increases microgliosis, impairs phagocytosis, and increases plaque load; causes deficits in spatial learning [72]; enhances microglial phagocytosis [161] | Enhances endocytosis of Aβ [72]; reduces microgliosis [72,163]; enhances microglia phagocytosis and co-localization with Aβ [162] |
Astrocytes | Disease-specific transcriptional profile; increased synaptic pruning; myelin debris accumulation; disruption of synapse number and morphology [168]; astrogliosis and white matter damage [169]; tau accumulation [170] | Increases astrogliosis [148,171,172,183,184]; disrupts autophagy–lysosomal system [149,171,178]; promotes synaptic degeneration, neuronal stress, and TDP-43 proteinopathy [168]; contributes to BBB disruption [185] | Attenuates pro-inflammatory activation of astrocytes [184]; decreased glial fibrillary acidic protein (GFAP) intensity [179]; number of astrocytes decreased [174] | No studies identified | Reduces astrogliosis [163] |
2.6. Therapeutic Modulation of PGRN
3. Conclusions
Author Contributions
Funding
Acknowledgments
Conflicts of Interest
Abbreviations
Abbreviation | Definition |
AAV | Adeno-associated viral vector. |
AAV1 | Adeno-associated viral vector serotype 1. |
AAV9 | Adeno-associated viral vector serotype 9. |
AD | Alzheimer’s disease. |
ALS | Amyotrophic lateral sclerosis. |
ALSP | Adult-onset leukoencephalopathy with axonal spheroids and pigmented glia. |
Aβ | Amyloid-β. |
BBB | Blood–brain barrier. |
bvFTD | Behavioral variant frontotemporal dementia. |
CNS | Central nervous system. |
CSF | Cerebrospinal fluid. |
CTSD | Cathepsin D. |
ERK/p90RSK | Extracellular-signal-regulated kinase/90 kiladalton ribosomal s6 kinase. |
FTD | Frontotemporal dementia. |
FTD-GRN | Frontotemporal dementia caused by progranulin gene mutation. |
FTLD | Frontotemporal lobar degeneration. |
FUS | Fused in sarcoma. |
GCase | β -glucocerebrosidase. |
GRN | Progranulin gene. |
iMG | iPSC microglia. |
iPSC | Induced pluripotent stem cells. |
LATE | Limbic-predominant age-related transactivation response deoxyribonucleic acid binding protein 43 encephalopathy. |
LOF | Loss of function. |
LRP1 | Low-density lipoprotein receptor-related protein. |
M6PR | Mannose 6-phosphate receptor. |
MCI | Mild cognitive impairment. |
MS | Multiple sclerosis. |
MS4A | Membrane-spanning 4-domains subfamily A. |
NCL | Neuronal ceroid lipofuscinosis. |
NFT | Neurofibrillary tangles. |
nfvPPA | Non-fluent variant primary progressive aphasia. |
PD | Parkinson’s disease. |
PET | Positron emission tomography. |
PGRN | Progranulin. |
PI3K/Akt | Phosphoinositide 3-kinase/protein kinase B. |
PPA | Primary progressive aphasia. |
PSAP | Prosaposin. |
ROS | Reactive oxygen species. |
SLPI | Secretory leukocyte peptidase inhibitor. |
SOD1 | Superoxide dismutase type 1. |
sPLA2-IIA | Type IIA secreted phospholipase A2. |
svPPA | Semantic variant primary progressive aphasia. |
TDP-43 | Transactivation response deoxyribonucleic acid binding protein 43. |
TFEB | Transcription factor EB. |
TNF | Tumor necrosis factor. |
TNF-α | Tumor necrosis factor alpha. |
TNFR1 | Tumor necrosis factor receptor 1. |
TNFR2 | Tumor necrosis factor receptor 2. |
Tregs | Regulatory T cells. |
sTREM2 | Soluble triggering receptor expressed on myeloid cells 2. |
TREM2 | Triggering receptor expressed on myeloid cells 2. |
Vps10p | Vacuolar protein sorting 10 protein. |
WBC | White blood cell. |
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Boylan, M.A.; Pincetic, A.; Romano, G.; Tatton, N.; Kenkare-Mitra, S.; Rosenthal, A. Targeting Progranulin as an Immuno-Neurology Therapeutic Approach. Int. J. Mol. Sci. 2023, 24, 15946. https://doi.org/10.3390/ijms242115946
Boylan MA, Pincetic A, Romano G, Tatton N, Kenkare-Mitra S, Rosenthal A. Targeting Progranulin as an Immuno-Neurology Therapeutic Approach. International Journal of Molecular Sciences. 2023; 24(21):15946. https://doi.org/10.3390/ijms242115946
Chicago/Turabian StyleBoylan, Maria A., Andrew Pincetic, Gary Romano, Nadine Tatton, Sara Kenkare-Mitra, and Arnon Rosenthal. 2023. "Targeting Progranulin as an Immuno-Neurology Therapeutic Approach" International Journal of Molecular Sciences 24, no. 21: 15946. https://doi.org/10.3390/ijms242115946
APA StyleBoylan, M. A., Pincetic, A., Romano, G., Tatton, N., Kenkare-Mitra, S., & Rosenthal, A. (2023). Targeting Progranulin as an Immuno-Neurology Therapeutic Approach. International Journal of Molecular Sciences, 24(21), 15946. https://doi.org/10.3390/ijms242115946