Frontotemporal lobar degeneration represents 10-20% of all dementias and is clinically important because of its earlier age of onset compared to Alzheimer's disease (AD), and its dramatic impact on core human qualities including personality, insight and verbal communication. We recently found that loss-of- function mutations in the gene encoding the secreted growth factor progranulin (PGRN) are an important cause of the most common pathological subtype of FTLD, characterized by neuronal inclusions composed of ubiquitinated TAR DNA-binding protein 43 (TDP43) (FTLD-U). Our working hypothesis is that mutations in PGRN are a more frequent cause of FTLD then initially anticipated and that subtle deregulation of PGRN expression may increase the susceptibility to develop FTLD and a wider range of neurodegenerative diseases. The identification of TDP43 as the pathological protein, not only in FTLD-U, but also in patients with amyotrophic lateral sclerosis (ALS) and in 20-30% of pathologically confirmed AD patients, supports a unifying disease mechanism underlying these disorders.
The specific aims of this project are to: 1. Identify the complete spectrum and frequency of mutations in PGRN. In the largest collection of FTLD patients worldwide, we will perform a standardized in- depth mutation screening of PGRN, supplemented with in-vitro functional analyses to determine the disease significance of novel mutations. 2. Identify regulatory cis-acting variants in PGRN that modify disease risk, penetrance or presentation in TDP43 proteinopathies. We will perform genetic association studies of PGRN in FTLD, ALS and AD case-control populations and assess the effect of common PGRN genetic variability on gene expression. 3. Determine the role of miR-659 expression and genetic variability in the development of FTLD. We recently made significant progress in the understanding of the regulation of PGRN when we identified that its expression can be regulated by a specific micro RNA, miR-659. Moreover, we have generated preliminary data suggesting that the common genetic variant rs5848, located in the 3'UTR of PGRN in a predicted binding-site for miR-659, is a major risk factor for FTLD-U through the augmented suppression of PGRN by miR-659. We will perform genetic and expression analyses to determine if deregulation of miR-659 expression in brain or altered genetic variability in the gene encoding miR-659 may contribute directly to the pathogenesis of FTLD-U The proposed studies are relevant to fully appreciate the contribution of PGRN mutations in FTLD leading to increased diagnostic accuracy and counseling. Unveiling the genetic and molecular pathways regulating PGRN may also reveal novel targets that can be exploited for therapeutic actions aimed at delaying the neurodegenerative disease process.

Public Health Relevance

This proposal is designed to define the complete PGRN mutational spectrum in FTLD and to determine whether subtle deregulation of PGRN expression may hold susceptibility to a wider range of neurodegenerative diseases. These studies are relevant to fully appreciate the contribution of PGRN mutations in FTLD leading to increased diagnostic accuracy and counseling. Unveiling the genetic and molecular pathways regulating PGRN may also reveal novel therapeutic targets that can be exploited for therapeutic actions aimed at delaying the neurodegenerative disease process.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS065782-04
Application #
8268462
Study Section
Genetics of Health and Disease Study Section (GHD)
Program Officer
Sutherland, Margaret L
Project Start
2009-06-01
Project End
2014-05-31
Budget Start
2012-06-01
Budget End
2014-05-31
Support Year
4
Fiscal Year
2012
Total Cost
$327,994
Indirect Cost
$113,619
Name
Mayo Clinic Jacksonville
Department
Type
DUNS #
153223151
City
Jacksonville
State
FL
Country
United States
Zip Code
32224
Kertesz, A; Finger, E; Murrell, J et al. (2015) Progressive supranuclear palsy in a family with TDP-43 pathology. Neurocase 21:178-84
Fujioka, Shinsuke; Boeve, Bradley F; Parisi, Joseph E et al. (2014) A familial form of parkinsonism, dementia, and motor neuron disease: a longitudinal study. Parkinsonism Relat Disord 20:1129-34
Xi, Zhengrui; Yunusova, Yana; van Blitterswijk, Marka et al. (2014) Identical twins with the C9orf72 repeat expansion are discordant for ALS. Neurology 83:1476-8
van Blitterswijk, Marka; Mullen, Bianca; Heckman, Michael G et al. (2014) Ataxin-2 as potential disease modifier in C9ORF72 expansion carriers. Neurobiol Aging 35:2421.e13-7
Ferrari, Raffaele; Hernandez, Dena G; Nalls, Michael A et al. (2014) Frontotemporal dementia and its subtypes: a genome-wide association study. Lancet Neurol 13:686-99
Hallam, Bradley J; Jacova, Claudia; Hsiung, Ging-Yuek R et al. (2014) Early neuropsychological characteristics of progranulin mutation carriers. J Int Neuropsychol Soc 20:694-703
Sitek, Emilia J; Narozanska, Ewa; Barczak, Anna et al. (2014) Agraphia in patients with frontotemporal dementia and parkinsonism linked to chromosome 17 with P301L MAPT mutation: dysexecutive, aphasic, apraxic or spatial phenomenon? Neurocase 20:69-86
Bit-Ivan, Esther N; Suh, Eunran; Shim, Hyung-Sub et al. (2014) A novel GRN mutation (GRN c.708+6_+9delTGAG) in frontotemporal lobar degeneration with TDP-43-positive inclusions: clinicopathologic report of 6 cases. J Neuropathol Exp Neurol 73:467-73
Lee, Wing C; Almeida, Sandra; Prudencio, Mercedes et al. (2014) Targeted manipulation of the sortilin-progranulin axis rescues progranulin haploinsufficiency. Hum Mol Genet 23:1467-78
van Blitterswijk, Marka; Mullen, Bianca; Wojtas, Aleksandra et al. (2014) Genetic modifiers in carriers of repeat expansions in the C9ORF72 gene. Mol Neurodegener 9:38

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