Targeted progranulin therapy for TDP-43 proteinopathy

The National Institute on Aging awarded the University of Alabama at Birmingham $486,779 on September 1, 2026, under the Aging Research program (CFDA 93.866) for research into targeted progranulin therapy as a treatment for TDP-43 proteinopathy, a primary pathology of amyotrophic lateral sclerosis, frontotemporal dementia, and a common co-pathology of Alzheimer's disease.

The research investigates whether boosting progranulin levels can provide neuroprotection in TDP-43 proteinopathy by distinguishing among multiple mechanisms through which progranulin acts. The project tests targeted delivery of progranulin directly to lysosomes without secretion, using a molecular targeting strategy designed to optimize the efficacy and safety of progranulin-boosting therapies beyond existing clinical trials limited to individuals with progranulin mutations.

Work is performed in Birmingham, Alabama. The period of performance runs from September 1, 2026, through August 31, 2027.

Abstract

TDP-43 proteinopathy is the primary pathology of ALS and ~45% of frontotemporal dementia (FTD-TDP), and is a common CO-pathology of alzheimer's disease. TDP-43 proteinopathy is associated with neuronal loss and clinical decline in these diseases, and currently has no disease-modifying therapies. Genetic data reveal a relationship between TDP-43 proteinopathy and low levels of progranulin, though the mechanism underlying this relationship is still unclear. Progranulin (GRN) mutations, which typically cause progranulin haploinsufficiency, cause FTD-TDP, so progranulin-boosting therapies have entered clinical trials for people with GRN mutations. Boosting progranulin levels is also neuroprotective in wild-type neurons, and progranulin overexpression reduces neuronal dysfunction after TDP-43 overexpression or knockdown. Though IT is unclear if these protective effects are due to regulation of TDP-43, these data raise the possibility that progranulin-boosting therapies may be useful for treating sporadic TDP-43 proteinopathy. This could have a significant therapeutic impact, but sustained elevation of progranulin may have several adverse side effects. Understanding the mechanism of progranulin's protective effects will thus be critical for optimizing the efficacy and safety of these therapies. Progranulin is a pro-protein that may act through multiple molecular targets, so we have investigated targeted progranulin delivery as a way to optimize progranulin-boosting therapy. Progranulin is constitutively secreted and engages in extracellular signaling before being trafficked to lysosomes, where IT facilitates hydrolase activity. IT is not clear which of these actions mediates progranulin's protective effects. To distinguish these mechanisms, we adopted a molecular targeting strategy to deliver progranulin to lysosomes without secretion (l-pgrn). Based on preliminary data, we propose to test the hypothesis that delivering progranulin to neuronal lysosomes will protect against TDP-43 proteinopathy. In aim 1 we will use novel l-pgrn knock-in mice, in which progranulin maintains lysosomal function but is not secreted, to test the hypothesis that progranulin's actions in lysosomes are sufficient to prevent the TDP-43 dysregulation observed in progranulin-insufficient mice. In aim 2, we will use progranulin (pgrn) or l-pgrn viral vectors in primary cortical and ipsc-derived neurons to test the hypothesis that boosting progranulin will reduce TDP-43 mislocalization from the nucleus and/or promote clearance of cytoplasmic TDP-43. We will also determine if any protective effects are dependent on autophagy or the critical protease cathepsin d. In aim 3 we will test whether AAV-pgrn or l-pgrn protect against TDP-43 dysregulation and neuronal dysfunction in TDP-43 mutant ipsc- derived neurons and two TDP-43 mouse lines. These studies will provide comprehensive preclinical data on progranulin-boosting therapy for TDP-43 proteinopathy, and determine the key cellular compartment for progranulin delivery. This could have immediate impact by guiding choice of therapies that preferentially increase extracellular or intracellular progranulin.