During the last fiscal year, we have completed two projects that are directly relevant to unraveling the genetic causes of frontotemporal dementia (FTD). In the first project, we used exome sequencing to identify a coding mutation in the valosin-containing protein (VCP) gene in an Italian family with autosomal dominantly inherited amyotrophic lateral sclerosis (ALS). This is directly relevant to FTD research, as mutations in VCP have previously been identified in families with Frontotemporal Dementia associated with Inclusion Body Myopathy and Pagets disease (IBMPFD). Screening of VCP in a cohort of 210 familial ALS cases and autopsy-proven ALS and ALS-FTD cases identified four additional mutations including a mutation in a pathologically proven case of ALS. VCP protein is essential for maturation of ubiquitin-containing autophagosomes, and mutant VCP toxicity is partially mediated through its effect on TDP-43 protein, a major constituent of ubiquitin inclusions that neuropathologically characterize ALS. Our data broaden the phenotype of IBMPFD to include motor neuron degeneration, suggest that VCP mutations may account for ∼1%-2% of familial ALS, and provide evidence directly implicating defects in the ubiquitination/protein degradation pathway in motor neuron degeneration, as well as frontal cortical regions. Furthermore, our work shows that it is possible to apply next generation sequencing techniques to successfully find causative genes in late-onset neurodegenerative diseases of aging, and provides further evidence that ALS and FTD share a common genetic etiology. This paper was published in Neuron in December 2010. In the second project, we published the results of our genome-wide association study of ALS (and ALS associated with FTD) in Finland. Finland is an ideal location for a genome-wide association study of these age-related neurodegenerative diseases because the incidence of this disease spectrum is one of the highest in the world, and because the genetic homogeneity of the Finnish population enhances the ability to detect risk loci. We identified two association peaks that exceeded genome-wide significance. One was located on chromosome 21q22, which corresponds to the autosomal recessive D90A allele of the SOD1 gene. The other was detected in a 232kb block of linkage disequilibrium in a region of chromosome 9p that was previously identified in linkage studies of families with ALS. Within this region, we defined a 42-SNP haplotype that was associated with significantly increased risk of ALS, and which overlapped with an association locus recently reported for frontotemporal dementia. For the 93 patients with familial ALS, the population attributable risk for the chromosome 9p21 locus was 37.9% (95% CI 27.7-48.1) and that for D90A homozygosity was 25.5% (16.9-34.1). These data clearly show that the chromosome 9p21 locus is a major cause of familial ALS in the Finnish population. Furthermore, the overlap with the risk haplotype recently reported for frontotemporal dementia provides further evidence of a shared genetic cause for these two neurodegenerative diseases. This paper was published in Lancet Neurology in October 2010. In summary, the current year has been successful in identifying genetic variants important in the pathogenesis of FTD using next generation sequencing and genome-wide association approaches. Our data also helps to unify FTD and ALS into a single disease rubic that encompasses two of the major late-onset neurodegenerative diseases. Each of the two studies employed large cohorts of research subjects, and utilized the sequencing and genotyping facilities available within the Laboratory of Neurogenetics, NIA.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Investigator-Initiated Intramural Research Projects (ZIA)
Project #
1ZIAAG000934-03
Application #
8335972
Study Section
Project Start
Project End
Budget Start
Budget End
Support Year
3
Fiscal Year
2011
Total Cost
$209,482
Indirect Cost
Name
National Institute on Aging
Department
Type
DUNS #
City
State
Country
Zip Code
Fratta, Pietro; Polke, James M; Newcombe, Jia et al. (2015) Screening a UK amyotrophic lateral sclerosis cohort provides evidence of multiple origins of the C9orf72 expansion. Neurobiol Aging 36:546.e1-7
Zhang, Ming; Xi, Zhengrui; Zinman, Lorne et al. (2015) Mutation analysis of CHCHD10 in different neurodegenerative diseases. Brain 138:e380
Diekstra, Frank P; Van Deerlin, Vivianna M; van Swieten, John C et al. (2014) C9orf72 and UNC13A are shared risk loci for amyotrophic lateral sclerosis and frontotemporal dementia: a genome-wide meta-analysis. Ann Neurol 76:120-33
Pliner, Hannah A; Mann, David M; Traynor, Bryan J (2014) Searching for Grendel: origin and global spread of the C9ORF72 repeat expansion. Acta Neuropathol 127:391-6
Kaivorinne, Anna-Lotta; Moilanen, Virpi; Kervinen, Marko et al. (2014) Novel TARDBP sequence variant and C9ORF72 repeat expansion in a family with frontotemporal dementia. Alzheimer Dis Assoc Disord 28:190-3
Pletnikova, Olga; Sloane, Kelly L; Renton, Alan E et al. (2014) Hippocampal sclerosis dementia with the C9ORF72 hexanucleotide repeat expansion. Neurobiol Aging 35:2419.e17-21
Traynor, Bryan J (2014) A roadmap for genetic testing in ALS. J Neurol Neurosurg Psychiatry 85:476
Su, Zhaoming; Zhang, Yongjie; Gendron, Tania F et al. (2014) Discovery of a biomarker and lead small molecules to target r(GGGGCC)-associated defects in c9FTD/ALS. Neuron 83:1043-50
Donnelly, Christopher J; Zhang, Ping-Wu; Pham, Jacqueline T et al. (2013) RNA toxicity from the ALS/FTD C9ORF72 expansion is mitigated by antisense intervention. Neuron 80:415-28
Kaivorinne, Anna-Lotta; Bode, Michaela K; Paavola, Liisa et al. (2013) Clinical Characteristics of C9ORF72-Linked Frontotemporal Lobar Degeneration. Dement Geriatr Cogn Dis Extra 3:251-62

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