Chemical and genetic rescue of in vivo progranulin-deficient lysosomal and autophagic defects.

Abstract

In 2006, GRN mutations were first linked to frontotemporal dementia (FTD), the leading cause of non-Alzheimer dementias. While much research has been dedicated to understanding the genetic causes of the disease, our understanding of the mechanistic impacts of GRN deficiency has only recently begun to take shape. With no known cure or treatment available for GRN-related FTD, there is a growing need to rapidly advance genetic and/or small-molecule therapeutics for this disease. This issue is complicated by the fact that, while lysosomal dysfunction seems to be a key driver of pathology, the mechanisms linking a loss of GRN to a pathogenic state remain unclear. In our attempt to address these key issues, we have turned to the nematode, Caenorhabditis elegans, to model, study, and find potential therapies for GRN-deficient FTD. First, we show that the loss of the nematode GRN ortholog, pgrn-1, results in several behavioral and molecular defects, including lysosomal dysfunction and defects in autophagic flux. Our investigations implicate the sphingolipid metabolic pathway in the regulation of many of the in vivo defects associated with pgrn-1 loss. Finally, we utilized these nematodes as an in vivo tool for high-throughput drug screening and identified two small molecules with potential therapeutic applications against GRN/pgrn-1 deficiency. These compounds reverse the biochemical, cellular, and functional phenotypes of GRN deficiency. Together, our results open avenues for mechanistic and therapeutic research into the outcomes of GRN-related neurodegeneration, both genetic and molecular.

Adjusted vascular contractility relies on integrity of progranulin pathway: Insights into mitochondrial function

“…In neuronal 42 and renal cells 41 and in C. elegans 50 PGRN acts as a regulator of mitochondrial function via preserving mitochondrial dynamics, biogenesis, and mitochondrial recycling. Mitochondrial dysfunction is part of premature ageing and contributes to appearance of inflammation, mitochondria-associated oxidative stress, cell senescence, and apoptosis, which are leading causes of CVD 39,51,52 including atherosclerosis and aneurysm 53-55 .…”

“…In neuronal 42 and renal cells 41 and in C. elegans 50 PGRN acts as a regulator of mitochondrial function via preserving mitochondrial dynamics, biogenesis, and mitochondrial recycling.…”

Simple models to understand complex disease: 10 years of progress from Caenorhabditis elegans models of amyotrophic lateral sclerosis and frontotemporal lobar degeneration

“…Evidence exists in C. elegans that both gain and loss of function mechanisms could be at play in neurodegeneration by fALS gene HnRNPA2B1 , KIF5A, and VABP ( Han et al, 2013 ; Zhang et al, 2017 ). Finally, the role of GRN and RAB38 mutations in FTLD have been studied in C. elegans models ( Grill et al, 2007 ; Salazar et al, 2015 ; Doyle et al, 2021 ).…”

“…RNAi knockdown of cgt-3/UGCG and asah-1/ASAH1 , also involved in sphingolipid metabolism, rescue prgn-1 mutant motor deficits. A screen of molecular compounds in this model uncovered two drugs, Rivastigmine and Rottlerin, which rescue pgrn-1 mutant motor and autophagy deficits and had a prolonged positive effect in a cell culture model ( Doyle et al, 2021 ). In another C. elegans model expressing human TDP-43, heterozygous deletion of pgrn-1(tm985) worsens motor deficits.…”

Multiple Molecular Pathways Are Influenced by Progranulin in a Neuronal Cell Model–A Parallel Omics Approach

“…Progranulin has multiple biological actions. It is neurotrophic ( Van Damme et al, 2008 ; Ryan et al, 2009 ), it down-regulates microglial neuroinflammation ( Martens et al, 2012 ), and it influences both lysosomal activity ( Kao et al, 2017 ; Paushter et al, 2018 ; Elia et al, 2019 ) and autophagy ( Chang et al, 2017 ; Elia et al, 2019 ; Doyle et al, 2021 ). Understanding how PGRN affects neuronal biology will provide insights into brain aging and resilience against neurodegeneration.…”