Approaches to develop therapeutics to treat frontotemporal dementia

• Published in: Neuropharmacology Vol. 166; p. 107948
• Main Authors: Elia, Lisa P., Reisine, Terry, Alijagic, Amela, Finkbeiner, Steven
• Format: Journal Article
• Language: English
• Published: England Elsevier Ltd 01-04-2020
• Subjects: Animals; Frontal Lobe - drug effects; Frontal Lobe - metabolism; Frontotemporal Dementia - genetics; Frontotemporal Dementia - metabolism; Frontotemporal Dementia - therapy; FTD; Genetic Therapy - trends; HSP90 Heat-Shock Proteins - antagonists & inhibitors; HSP90 Heat-Shock Proteins - metabolism; Humans; Lysosome; Neurodegenerative; Progranulin; Progranulins - agonists; Progranulins - metabolism; Quinolones - pharmacology; Quinolones - therapeutic use; Temporal Lobe - drug effects; Temporal Lobe - metabolism; Therapeutics; Tyrosine - analogs & derivatives; Tyrosine - pharmacology; Tyrosine - therapeutic use; AD; Progranulin; Neurodegenerative; FTD; Lysosome; Therapeutics
• ISSN: 0028-3908; 1873-7064
• DOI: 10.1016/j.neuropharm.2020.107948

Frontotemporal degeneration (FTD) is a complex disease presenting as a spectrum of clinical disorders with progressive degeneration of frontal and temporal brain cortices and extensive neuroinflammation that result in personality and behavior changes, and eventually, death. There are currently no effective therapies for FTD. While 60–70% of FTD patients are sporadic cases, the other 30–40% are heritable (familial) cases linked to mutations in several known genes. We focus here on FTD caused by mutations in the GRN gene, which encodes a secreted protein, progranulin (PGRN), that has diverse roles in regulating cell survival, immune responses, and autophagy and lysosome function in the brain. FTD-linked mutations in GRN reduce brain PGRN levels that lead to autophagy and lysosome dysfunction, TDP43 accumulation, excessive microglial activation, astrogliosis, and neuron death through still poorly understood mechanisms. PGRN insufficiency has also been linked to Alzheimer's disease (AD), and so the development of therapeutics for GRN-linked FTD that restore PGRN levels and function may have broader application for other neurodegenerative diseases. This review focuses on a strategy to increase PGRN to functional, healthy levels in the brain by identifying novel genetic and chemical modulators of neuronal PGRN levels.
This article is part of the special issue entitled ‘The Quest for Disease-Modifying Therapies for Neurodegenerative Disorders’.
•Frontotemporal dementia is the second prevalent dementia after Alzheimer's disease.•GRN mutations leading to PGRN deficiency are linked to frontotemporal dementia.•PGRN deficiency causes lysosome defects, neurodegeneration, and neuroinflammation.•Efforts to raise PGRN levels are a therapeutic strategy for frontotemporal dementia.