Format

Send to

Choose Destination
J Neurosci. 2019 Jan 29. pii: 3498-17. doi: 10.1523/JNEUROSCI.3498-17.2019. [Epub ahead of print]

Genetic Regulation of Neuronal Progranulin Reveals a Critical Role for the Autophagy-Lysosome Pathway.

Author information

1
Center for Systems and Therapeutics and Taube/Koret Center for Neurodegenerative Disease Research, San Francisco, CA lisa.elia@gladstone.ucsf.edu steve.finkbeiner@gladstone.ucsf.edu.
2
The J. David Gladstone Institutes, San Francisco, CA.
3
Keck School of Medicine of USC, Los Angeles, CA.
4
Departments of Neurology and Physiology, UCSF, San Francisco, CA.

Abstract

Deficient progranulin levels cause dose-dependent neurological syndromes: haploinsufficiency leads to frontotemporal lobar degeneration (FTLD), and nullizygosity produces adult-onset neuronal ceroid lipofuscinosis. Mechanisms controlling progranulin levels are largely unknown. To better understand progranulin regulation, we performed a genome-wide RNAi screen using an ELISA-based platform to discover genes that regulate progranulin levels in neurons. We identified 830 genes that raise or lower progranulin levels by at least 1.5-fold in Neuro2a cells. When inhibited by siRNA or some by submicromolar concentrations of small-molecule inhibitors, 33 genes of the druggable genome increased progranulin levels in mouse primary cortical neurons; several of these also raised progranulin levels in FTLD-model mouse neurons. "Hit" genes regulated progranulin by transcriptional or post-transcriptional mechanisms. Pathway analysis revealed enrichment of hit genes from the autophagy-lysosome pathway (ALP), suggesting a key role for this pathway in regulating progranulin levels. Progranulin itself regulates lysosome function. We found progranulin-deficiency in neurons increased autophagy and caused abnormally enlarged lysosomes, and boosting progranulin levels restored autophagy and lysosome size to control levels. Our data link the ALP to neuronal progranulin: progranulin levels are regulated by autophagy, and in turn, progranulin regulates the ALP. Restoring progranulin levels by targeting genetic modifiers reversed FTLD functional deficits, opening up potential opportunities for future therapeutics development.SIGNIFICANCE STATEMENTProgranulin regulates neuron and immune functions, and is implicated in aging. Loss of one functional allele causes haploinsufficiency and leads to frontotemporal lobar degeneration (FTLD), the second leading cause of dementia. Progranulin gene polymorphisms are linked to Alzheimer's disease (AD) and complete loss of function causes neuronal ceroid lipofuscinosis. Despite the critical role of progranulin levels in neurodegenerative disease risk, almost nothing is known about their regulation. We performed an unbiased screen and identified specific pathways controlling progranulin levels in neurons. Modulation of these pathways restored levels in progranulin-deficient neurons and reversed FTLD phenotypes. We provide a new comprehensive understanding of the genetic regulation of progranulin levels, and identify potential targets to treat FTLD and other neurodegenerative diseases, including AD.

Supplemental Content

Full text links

Icon for HighWire
Loading ...
Support Center