Abstract
Progranulin (PGRN) is critical in supporting a healthy CNS. Its haploinsufficiency results in frontotemporal dementia, while in experimental models of age-related neurodegenerative diseases, the targeted expression of PGRN greatly slows the onset of disease phenotypes. Nevertheless, much remains unclear about how PGRN affects its target cells. In previous studies we found that PGRN showed a remarkable ability to support the survival of NSC-34 motor neuron cells under conditions that would otherwise lead to their apoptosis. Here we used the same model to investigate other phenotypes of PGRN expression in NSC-34 cells. PGRN significantly influenced morphological differentiation, resulting in cells with enlarged cell bodies and extended projections. At a molecular level this correlated with pathways associated with the cytoskeleton and synaptic differentiation. Depletion of PGRN led to increased expression of several neurotrophic receptors, which may represent a homeostatic mechanism to compensate for loss of neurotrophic support from PGRN. The exception was RET, a neurotrophic tyrosine receptor kinase, which, when PGRN levels are high, shows increased expression and enhanced tyrosine phosphorylation. Other receptor tyrosine kinases also showed higher tyrosine phosphorylation when PGRN was elevated, suggesting a generalized enhancement of receptor activity. PGRN was found to bind to multiple plasma membrane proteins, including RET, as well as proteins in the ER/Golgi apparatus/lysosome pathway. Understanding how these various pathways contribute to PGRN action may provide routes toward improving neuroprotective therapies.
Highlights
Neurodegenerative diseases of aging are a leading cause of death, disability, and dependency (Erkkinen et al, 2018)
Heterozygous non-sense mutations of GRN that result in a loss of 50% of PGRN mRNA, cause FTD-GRN, a form of frontotemporal dementia that results from a progressive cortical
PGRN levels were depleted by approximately 50% in NSC-34/shPGRN cells, a reduction equivalent to that associated with FTD-GRN (Supplementary Figures 1A,B)
Summary
Neurodegenerative diseases of aging are a leading cause of death, disability, and dependency (Erkkinen et al, 2018). Heterozygous non-sense mutations of GRN that result in a loss of 50% of PGRN mRNA, cause FTD-GRN, a form of frontotemporal dementia that results from a progressive cortical. Some variants of the GRN gene act as modifiers of ALS progression, reducing the age of onset of the disease and shortening survival (Sleegers et al, 2008). Both alleles of GRN are mutated, leading to the complete loss of PGRN mRNA and resulting in a lysosomal storage disorder called neuronal ceroid lipofuscinosis (NCL) (Smith et al, 2012). The role of GRN-deficiency in FTD has prompted interest in the development of PGRN-based therapies by, for example, increasing PGRN levels in the brain (Arrant et al, 2017, 2018; Miyakawa et al, 2020), or promoting read-through of GRN non-sense mutations (Frew et al, 2020; Kuang et al, 2020)
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