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Role of Progranulin

Progranulin (PGRN) may be the key to many neurodegenerative diseases

  • PGRN is a protein made by the GRN gene which plays a critical role in safeguarding the health and survival of different typesof cells
  • PGRN is mainly expressed by microglial cells (immune cells of the brain) and neurons in the central nervous system (CNS). Sufficient levels are important to help cells survive, grow, and control inflammation
Typical PGRN levels and Reduced PGRN levels

Why PGRN levels matter

In several neurodegenerative diseases, PGRN deficiency may lead to neuronal dysfunction in a number of ways, including:

  • Lysosomal dysfunction (impairment of the ability of lysosomes—an organelle found inside cells—to breakdown misfolded proteins)
  • Activation of the microglial inflammatory response
  • Synaptic disruption (reduced ability of cells in the brain to communicate with one another)
  • Transactive response DNA binding protein 43 kDa (TDP-43) pathology (an abnormal accumulation ofTDP-43 proteins in neurons)
PGRN levels PGRN levels

Reduced PGRN levels have been implicated as a risk factor for many devastating neurodegenerativediseases including:

  • Frontotemporal dementia (FTD)
  • Amyotrophic lateral sclerosis (ALS)
  • Alzheimer’s disease (AD)
  • Parkinson’s disease (PD)

At Passage Bio, we are exploring the therapeutic potential of elevating PGRN levels in the CNS to alter the course of neurodegenerative diseases.

TDP-43 pathology: A hallmark of many neurodegenerative diseases

Understanding the link between PGRN and TDP-43 pathology

  • TDP-43 pathology appears to be a common feature in several neurodegenerative diseases including FTD-GRN and FTD-C9orf72, ~95% of patients with ALS, and ~50% patients with AD
  • In these neurodegenerative disease states, the normal function of TDP-43 in a cell's nucleus is reduced, and TDP-43 accumulates in the cytoplasm
  • TDP-43 pathology is common in neurodegenerative conditions where PGRN levels are depleted
TDP-43 pathology

Promising preclinical research

  • Preclinical studies in TDP-43 pathology models showed that elevated PGRN reduced cytoplasmic TDP-43 accumulation and slowed neurodegeneration
Promising preclinical research in TDP-43 pathology
Learn more about our cutting-edge pipeline