Lysosome dysfunction as a cause of neurodegenerative diseases: Lessons from frontotemporal dementia and amyotrophic lateral sclerosis

Root, Jessica; Merino, Paola; Nuckols, Austin; Johnson, Michelle; Kukar, Thomas

doi:10.1016/j.nbd.2021.105360

Cited by 113 publications

(126 citation statements)

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“…PGRN may affect lysosome acidification and thereby lysosomal enzyme activity (Logan et al, 2021;Tanaka et al, 2017). We and others have shown that PGRN deficiency results in upregulation of several lysosomal enzymes (Gotzl et al, 2018;Gotzl et al, 2014;Klein et al, 2017;Root et al, 2021).…”

Section: Discussionmentioning

confidence: 94%

Loss of TREM2 reduces hyperactivation of progranulin deficient microglia but not lysosomal pathology

Reifschneider

Robinson

et al. 2021

Preprint

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GRN haploinsufficiency causes frontotemporal lobar degeneration and results in microglial hyperactivation, lysosomal dysfunction and TDP-43 deposition. To understand the contribution of microglial hyperactivation to pathology we evaluated genetic and pharmacological approaches suppressing TREM2 dependent transition of microglia from a homeostatic to a disease associated state. Trem2 deficiency in Grn KO mice led to a reduction of microglia activation. To explore antibody-mediated pharmacological modulation of TREM2-dependent microglial states, we identified antagonistic TREM2 antibodies. Treatment of macrophages from GRN-FTLD patients with these antibodies allowed a complete rescue of elevated levels of TREM2 together with increased shedding and reduction of TREM2 signaling. Furthermore, antibody-treated PGRN deficient hiMGL showed dampened microglial hyperactivation, reduced TREM2 signaling and phagocytic activity, however, lack of rescue of lysosomal dysfunction. Similarly, lysosomal dysfunction, lipid dysregulation and glucose hypometabolism of Grn KO mice were not rescued by TREM2 ablation. Furthermore, NfL, a biomarker for neurodegeneration, was elevated in the Grn/Trem2 KO. These findings suggest that microglia hyperactivation is not necessarily contributing to neurotoxicity, and instead demonstrates that TREM2 exhibits neuroprotective potential in this model.

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Section: Discussionmentioning

confidence: 94%

Loss of TREM2 reduces hyperactivation of progranulin deficient microglia but not lysosomal pathology

Reifschneider

Robinson

et al. 2021

Preprint

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“…In this process, autophagosomes are an integral part of the autophagy cascade where they begin as phagophores that expand into autophagosomes and fuse with endosomes and lysosomes to allow degradation of the compartment contents (Longatti et al ., 2010). Dysfunctional autophagosome formation and other aspects of the autophagy-lysosome pathway has been widely reported in ALS and FTD (Root et al , 2021). In this study, we idented CLTA as a binding partner for FUS, which is involved autophagosome formation.…”

Section: Discussionmentioning

confidence: 99%

“…Nonetheless, it remains possible that phosphorylation of FUS, or expression of pathogenic FUS mutations, affects autophagy and related pathways (e.g. autophagic flux, lysosome health, fusion, endocytosis) (Klionsky et al , 2021; Root et al ., 2021). Future studies should examine whether other parts of the clathrin-mediated endocytic pathway are affected by expression of FUS PM leads to changes in function.…”

Section: Discussionmentioning

confidence: 99%

Proximity-based labeling reveals DNA damage-induced N-terminal phosphorylation of fused in sarcoma (FUS) leads to distinct changes in the FUS protein interactome

Merino

et al. 2021

Preprint

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Fused in sarcoma (FUS) is an RNA/DNA binding protein that normally resides in the nucleus. However, FUS forms pathologic cytoplasmic inclusions in two neurodegenerative disorders, frontotemporal lobar degeneration (FTLD) and amyotrophic lateral sclerosis (ALS). While a majority of ALS cases with FUS pathology can be explained by pathogenic mutations in the FUS gene, the vast majority of FTLD-FUS cases are not caused by FUS mutations and the reason why FUS forms inclusions is unknown. Therefore, identification of other non-genetic mechanisms that cause FUS to accumulate in the cytoplasm is crucial to understanding FTLD and ALS pathogenesis. To this end, DNA damage is known to trigger DNA-PK to phosphorylate FUS at N-terminal residues leading to FUS accumulation in the cytoplasm. However, the functional consequences of FUS phosphorylation are unknown. In this study, we performed proximity-dependent biotin labeling via ascorbate peroxidase 2 (APEX2) paired with mass spectrometry to investigate whether phosphorylation shifts the FUS interactome and protein function. Data are available via ProteomeXchange with identifier PXD026578. We identified a highly interrelated interactome between wild-type, phosphomimetic FUS (a proxy for phosphorylated FUS), and the pathogenic ALS-linked mutant P525L FUS. We demonstrate that expression of phosphomimetic FUS shifts the FUS interactome toward more cytoplasmic functions including mediation of mRNA metabolism and translation. Our findings reveal that phosphorylation of FUS may disrupt homeostatic translation and mRNA metabolism. These results highlight the importance of phosphorylation as a modulator of FUS interactions and functions with a potential link to disease pathogenesis.

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“…The precise role of GRNs in the pathophysiology of neurodegenerative disorders has remained an open question. In general, under what conditions and cellular cues are they generated from their percussor PGRN, and what role do they play in cellular functions and dysfunction has been a point of debate (Bateman, Belcourt, Bennett, Lazure, & Solomon, 1990;Bateman & Bennett, 1998;Holler et al, 2017;Horinokita et al, 2019;Kao, McKay, Singh, Brunet, & Huang, 2017;Root et al, 2021). What we do know is that PGRN secreted from microglia and astrocytes are transported into neuronal lysosomes by a sortilin-mediated pathway (Hu et al, 2010;Kao et al, 2017) and that the proteolytic processing generates GRNs within the lysosomes (Holler et al, 2017;Chris W. Lee et al, 2017) but what functional roles they play in lysosomes remain uncertain.…”

Section: Discussionmentioning

confidence: 99%

“…In this context, the cysteine-rich, ~6 kDa modules called granulins (GRNs 1-7), which are the proteolytic products of PGRN (Zhu et al, 2002) have been of great interest to us for their potential roles in FTLD and other related pathologies. It is now known that extracellular PGRN is endocytosed into the lysosome via a sortillin-mediated pathway to be processed by cathepsins into GRNs (C. W. Lee et al, 2017), which are thus speculated to possess lysosomal functions (Holler, Taylor, Deng, & Kukar, 2017;Root, Merino, Nuckols, Johnson, & Kukar, 2021). GRNs also function in a plethora of roles in normal cell biology (Park et al, 2011;Shoyab, McDonald, Byles, Todaro, & Plowman, 1990;Philip Van Damme et al, 2008) but possess opposing inflammatory properties to PGRN; while PGRN is anti-inflammatory, GRNs show proinflammatory properties (Zhu et al, 2002).…”

Section: Introductionmentioning

confidence: 99%

Cytoplasmic Colocalization of Granulins and TDP-43 Prion-like Domain Involves Electrostatically Driven Coacervation Tuned by the Redox State of Cysteines

Aa¹,

Dhakal

Rangachari

2021

Preprint

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Cytoplasmic inclusions containing aberrant proteolytic fragments of TDP-43 are associated with frontotemporal lobar degeneration (FTLD) and other related pathologies. In FTLD, TDP-43 is translocated into the cytoplasm and proteolytically cleaved to generate a prion-like domain (PrLD) containing C-terminal fragments (C25 and C35) that form toxic inclusions. Under stress, TDP-43 partitions into membraneless organelles called stress granules (SGs) by coacervating with RNA and other proteins. We were interested in understanding if and how cysteine-rich granulins (GRNs 1-7), which are the proteolytic products of a genetic risk factor in FTLD called progranulin, interact with TDP-43. We show that extracellular GRNs internalize and colocalize with PrLD as puncta in the cytoplasm of neuroblastoma cells but show no presence in SGs. In addition, GRNs and PrLD undergo liquid-liquid phase separation (LLPS) by complex coacervation, or form aggregates via liquid-solid phase separation (LSPS); the dynamics in these phase transitions appear to be driven by the negative charges on GRNs and fine-tuned by the positive charges and the redox state of cysteines. Furthermore, RNA competes with and expunges GRNs from GRN-PrLD condensates, providing a basis for GRN's absence in SGs. Together, the results bring to bear unique mechanisms by which GRNs could modulate TDP-43 proteinopathies.

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Lysosome dysfunction as a cause of neurodegenerative diseases: Lessons from frontotemporal dementia and amyotrophic lateral sclerosis

Cited by 113 publications

References 458 publications

Loss of TREM2 reduces hyperactivation of progranulin deficient microglia but not lysosomal pathology

Loss of TREM2 reduces hyperactivation of progranulin deficient microglia but not lysosomal pathology

Proximity-based labeling reveals DNA damage-induced N-terminal phosphorylation of fused in sarcoma (FUS) leads to distinct changes in the FUS protein interactome

Cytoplasmic Colocalization of Granulins and TDP-43 Prion-like Domain Involves Electrostatically Driven Coacervation Tuned by the Redox State of Cysteines

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