Ubiquitin positive inclusions are found in amyotrophic lateral sclerosis (ALS), a prototypic motor neuron disease and frontotemporal lobar degeneration (FTLD), the second most common dementia after Alzheimer's disease in patients <65. Recently, investigators at the University of Pennsylvania (PENN) identified TDP-43 as the disease protein ubiquitinated in both disorders. Since motor neuron disease and dementia are found in ALS and FTLD, and since the same disease protein accumulates in both disease entities, this suggests that ALS and FTLD represent the same clinicopathological spectrum of a neurodegenerative syndrome. Thus, the major goals of this Program Project Grant (PPG) is to develop a vigorous research program focused on elucidating the etiology and pathogenesis of TDP-43 proteinopathies in ALS without or with cognitive impairment or dementia (designated as ALS, ALS-Cog and ALS-FTLD, respectively) and compare them to FTLD with and without ALS. The investigators of this new PPG are a close-knit and highly integrated multidisciplinary group of PENN physicians and basic scientists who have formed a productive collaborative alliance and established a very comprehensive clinical and basic science research program at PENN to study ALS, ALS-Cog and ALS-FTLD in patients, in human postmortem tissues and in model systems. These investigators propose a set of bold objectives for ALS and FTLD research that will be implemented through 4 Cores and 3 Projects. Specifically, they will: 1) recruit ALS, ALS-Cog and ALS-FTLD patients;2) develop new algorithms to characterize the cognitive impairments and dementia in ALS patients;3) test the hypothesis that there is a tight link between language and motor systems in the representation of action verbs;4) further characterize the spectrum of TDP-43 neuropathologies in ALS, ALS-Cog and ALS-FTLD brains and compare them with FTLD with and without ALS;5) identify hyperphosphorylated residues and N-terminal cleavage sites that generate C-terminal fragments in pathological TDP-43 and determine their significance in mechanisms of TDP-43 proteinopathies;6) establish cell culture and transgenic mouse models of TDP-43;7) use these models to elucidate the pathogenic mechanisms of neurodegeneration in TDP-43;8) determine if genetic variants in TDP-43 found in patients with ALS, ALS-Cog and ALS-FTLD are disease risk factors or pathogenic disease causing mutations;These and other studies will lead to improved understanding of the cognitive impairments and dementia in ALS as well as provide insights on the diagnosis and treatment of these disorders.

Public Health Relevance

The basic, Clinical and translational studies proposed in the 4 Cores and 3 Projects here in this Program Project Grant represent an interdisciplinary, synergistic and complementary team effort to increase understanding of the cognitive impairments and dementia in amyotrophic lateral sclerosis (ALS) as well as provide insights on the diagnosis and treatment of ALS and its different clinical manifestations, especially those that affect cognition. Thus, this PPG addresses important questions in the field of ALS research.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Program Projects (P01)
Project #
5P01AG032953-05
Application #
8723014
Study Section
Special Emphasis Panel ()
Program Officer
Petanceska, Suzana
Project Start
2010-09-30
Project End
2015-05-31
Budget Start
2014-06-01
Budget End
2015-05-31
Support Year
5
Fiscal Year
2014
Total Cost
$1,157,186
Indirect Cost
$433,945
Name
University of Pennsylvania
Department
Pathology
Type
Schools of Medicine
DUNS #
042250712
City
Philadelphia
State
PA
Country
United States
Zip Code
19104
van Rheenen, Wouter; Shatunov, Aleksey; Dekker, Annelot M et al. (2016) Genome-wide association analyses identify new risk variants and the genetic architecture of amyotrophic lateral sclerosis. Nat Genet 48:1043-8
Irwin, David J; Byrne, Matthew D; McMillan, Corey T et al. (2016) Semi-Automated Digital Image Analysis of Pick's Disease and TDP-43 Proteinopathy. J Histochem Cytochem 64:54-66
Habes, Mohamad; Erus, Guray; Toledo, Jon B et al. (2016) White matter hyperintensities and imaging patterns of brain ageing in the general population. Brain 139:1164-79
Healey, Meghan L; Grossman, Murray (2016) Social Coordination in Older Adulthood: A Dual-Process Model. Exp Aging Res 42:112-7
Habes, M; Toledo, J B; Resnick, S M et al. (2016) Relationship between APOE Genotype and Structural MRI Measures throughout Adulthood in the Study of Health in Pomerania Population-Based Cohort. AJNR Am J Neuroradiol 37:1636-42
Gervits, Felix; Ash, Sharon; Coslett, H Branch et al. (2016) Transcranial direct current stimulation for the treatment of primary progressive aphasia: An open-label pilot study. Brain Lang 162:35-41
Pustina, Dorian; Coslett, H Branch; Turkeltaub, Peter E et al. (2016) Automated segmentation of chronic stroke lesions using LINDA: Lesion identification with neighborhood data analysis. Hum Brain Mapp 37:1405-21
Lee, Yune-Sang; Min, Nam Eun; Wingfield, Arthur et al. (2016) Acoustic richness modulates the neural networks supporting intelligible speech processing. Hear Res 333:108-17
Price, Amy Rose; Peelle, Jonathan E; Bonner, Michael F et al. (2016) Causal Evidence for a Mechanism of Semantic Integration in the Angular Gyrus as Revealed by High-Definition Transcranial Direct Current Stimulation. J Neurosci 36:3829-38
Ash, Sharon; Ternes, Kylie; Bisbing, Teagan et al. (2016) Dissociation of quantifiers and object nouns in speech in focal neurodegenerative disease. Neuropsychologia 89:141-52

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