TY - JOUR
T1 - Progranulin axis and recent developments in frontotemporal lobar degeneration
AU - Nicholson, Alexandra M.
AU - Gass, Jennifer
AU - Petrucelli, Leonard
AU - Rademakers, Rosa
N1 - Funding Information:
The work in the authors’laboratories is supported by NIH grants P50AG16574-13, R01NS065782-3, R01AG026251-03A2-1, R01NS063964-2 and R01NS077402-1, the ALS Association, the ALS Therapy Alliance and the Consortium for Frontotemporal Dementia. AMN is funded by the Association for Frontotemporal Degeneration Postdoctoral Fellowship.
PY - 2012
Y1 - 2012
N2 - Frontotemporal lobar degeneration (FTLD) is a devastating neurodegenerative disease that is the second most common form of dementia affecting individuals under age 65. The most common pathological subtype, FTLD with transactive response DNA-binding protein with a molecular weight of 43 kDa inclusions (FTLD-TDP), is often caused by autosomal dominant mutations in the progranulin gene (GRN) encoding the progranulin protein (PGRN). GRN pathogenic mutations result in haploinsufficiency, usually by nonsense-mediated decay of the mRNA. Since the discovery of these mutations in 2006, several groups have published data and animal models that provide further insight into the genetic and functional relevance of PGRN in the context of FTLD-TDP. These studies were critical in initiating our understanding of the role of PGRN in neural development, degeneration, synaptic transmission, cell signaling, and behavior. Furthermore, recent publications have now identified the receptors for PGRN, which will hopefully lead to additional therapeutic targets. Additionally, drug screens have been conducted to identify pharmacological regulators of PGRN levels to be used as potential treatments for PGRN haploinsufficiency. Here we review recent literature describing relevant data on GRN genetics, cell culture experiments describing the potential role and regulators of PGRN in the central nervous system, animal models of PGRN deficiency, and potential PGRN-related FTLD therapies that are currently underway. The present review aims to underscore the necessity of further elucidation of PGRN biology in FTLD-related neurodegeneration.
AB - Frontotemporal lobar degeneration (FTLD) is a devastating neurodegenerative disease that is the second most common form of dementia affecting individuals under age 65. The most common pathological subtype, FTLD with transactive response DNA-binding protein with a molecular weight of 43 kDa inclusions (FTLD-TDP), is often caused by autosomal dominant mutations in the progranulin gene (GRN) encoding the progranulin protein (PGRN). GRN pathogenic mutations result in haploinsufficiency, usually by nonsense-mediated decay of the mRNA. Since the discovery of these mutations in 2006, several groups have published data and animal models that provide further insight into the genetic and functional relevance of PGRN in the context of FTLD-TDP. These studies were critical in initiating our understanding of the role of PGRN in neural development, degeneration, synaptic transmission, cell signaling, and behavior. Furthermore, recent publications have now identified the receptors for PGRN, which will hopefully lead to additional therapeutic targets. Additionally, drug screens have been conducted to identify pharmacological regulators of PGRN levels to be used as potential treatments for PGRN haploinsufficiency. Here we review recent literature describing relevant data on GRN genetics, cell culture experiments describing the potential role and regulators of PGRN in the central nervous system, animal models of PGRN deficiency, and potential PGRN-related FTLD therapies that are currently underway. The present review aims to underscore the necessity of further elucidation of PGRN biology in FTLD-related neurodegeneration.
UR - http://www.scopus.com/inward/record.url?scp=84855219552&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84855219552&partnerID=8YFLogxK
U2 - 10.1186/alzrt102
DO - 10.1186/alzrt102
M3 - Review article
C2 - 22277331
AN - SCOPUS:84855219552
SN - 1758-9193
VL - 4
JO - Alzheimer's Research and Therapy
JF - Alzheimer's Research and Therapy
IS - 1
M1 - 4
ER -