Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disease that wreaks havoc on motor neurons. Recently, a central role for RNA binding proteins and RNA metabolism pathways has emerged. TDP-43 is an RNA binding protein that has been identified as a component of pathological inclusions in neurons of most ALS patients. Further, pathogenic mutations in the gene encoding TDP-43 (TARDBP) are associated with familial and sporadic ALS cases. These data argue that pathological activities of TDP-43 are critical to ALS. Despite the central importance of TDP-43, however, little is understood about how it causes disease and protein interaction partners that lead to ALS. This Co-PI research proposal brings together two experts in yeast and fly genetics who have made fundamental discoveries into mechanisms of devastating human age-related diseases such as Parkinson's disease and ALS using these simple but powerful systems. Importantly, discoveries made in yeast are translatable to Drosophila disease models, and from yeast and flies to human patients. Using these systems, we have found that ataxin-2, a polyglutamine (polyQ) protein, whose polyQ repeat expansions cause spinocerebellar ataxia type 2 (SCA2), is a potent modifier of TDP-43 toxicity in yeast and fly. Launching from this finding, we tested and found that polyQ expansions of 27-33Qs in the human ataxin-2 gene, ATXN2, are significantly associated with ALS. These data argue that ATXN2 is a new and relatively common ALS susceptibility disease gene, and that the TDP-43/Atx2 interaction is a critical target in ALS and perhaps other diseases associated with TDP-43 pathology. With the goal to reveal mechanistic insight into this interaction, we propose three Specific Aims.
In Aim 1, we will use mammalian cell culture and Drosophila to define the domains of the TDP-43 and ataxin-2 proteins that are critical for the synergistic interaction in degeneration and function. These studies will provide insight into the activity of the proteins and processes affected in the pathological situation.
In Aim 2, we will use the power of fly genetics to define additional genes critical for the synergy between TDP-43 and ataxin-2. This will reveal understanding of the processes perturbed and new pathways for therapeutic targeting. Finally, in Aim 3, we will address the greater role of ataxin-2 in neurodegeneration. ALS shares a disease spectrum with frontotemporal lobar degeneration (FTLD) and TDP- 43 pathology characterizes other neurodegenerative diseases. We will assess polyQ repeat lengths of ataxin-2 in other diseases to assess whether expansions occur in related disorders. Taken together, these findings will reveal key aspects of the TDP-43/ataxin-2 interaction central to ALS, the broader role of ataxin-2 in neurodegenerative disease, and the foundation for novel therapeutic insights.

Public Health Relevance

ALS and other neurodegenerative diseases are devastating for individuals and families involved;there are no cures and few treatments. Our studies have revealed a new gene, ataxin-2, whose mutation is a risk factor for ALS. The studies proposed will reveal insight into the role of ataxin-2 in this and other neurodegenerative diseases, providing mechanistic detail and the foundation for novel therapeutic approaches.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS073660-02
Application #
8322589
Study Section
Cellular and Molecular Biology of Neurodegeneration Study Section (CMND)
Program Officer
Gubitz, Amelie
Project Start
2011-09-01
Project End
2016-06-30
Budget Start
2012-07-01
Budget End
2013-06-30
Support Year
2
Fiscal Year
2012
Total Cost
$342,231
Indirect Cost
$123,481
Name
University of Pennsylvania
Department
Anatomy/Cell Biology
Type
Schools of Medicine
DUNS #
042250712
City
Philadelphia
State
PA
Country
United States
Zip Code
19104
Boeynaems, Steven; Bogaert, Elke; Michiels, Emiel et al. (2016) Drosophila screen connects nuclear transport genes to DPR pathology in c9ALS/FTD. Sci Rep 6:20877
Gitler, Aaron D; Tsuiji, Hitomi (2016) There has been an awakening: Emerging mechanisms of C9orf72 mutations in FTD/ALS. Brain Res 1647:19-29
Kramer, Nicholas J; Carlomagno, Yari; Zhang, Yong-Jie et al. (2016) Spt4 selectively regulates the expression of C9orf72 sense and antisense mutant transcripts. Science 353:708-12
McGurk, Leeanne; Berson, Amit; Bonini, Nancy M (2015) Drosophila as an In Vivo Model for Human Neurodegenerative Disease. Genetics 201:377-402
Burguete, Alondra Schweizer; Almeida, Sandra; Gao, Fen-Biao et al. (2015) GGGGCC microsatellite RNA is neuritically localized, induces branching defects, and perturbs transport granule function. Elife 4:e08881
Coyne, Alyssa N; Yamada, Shizuka B; Siddegowda, Bhavani Bagevalu et al. (2015) Fragile X protein mitigates TDP-43 toxicity by remodeling RNA granules and restoring translation. Hum Mol Genet 24:6886-98
Jovičić, Ana; Mertens, Jerome; Boeynaems, Steven et al. (2015) Modifiers of C9orf72 dipeptide repeat toxicity connect nucleocytoplasmic transport defects to FTD/ALS. Nat Neurosci 18:1226-9
Bonini, Nancy M; Hardiman, Orla (2015) Ataxin-2 expands insight into the ALS clinical spectrum. Neurology 84:224-5
Figley, Matthew D; Bieri, Gregor; Kolaitis, Regina-Maria et al. (2014) Profilin 1 associates with stress granules and ALS-linked mutations alter stress granule dynamics. J Neurosci 34:8083-97
Figley, Matthew D; Thomas, Anna; Gitler, Aaron D (2014) Evaluating noncoding nucleotide repeat expansions in amyotrophic lateral sclerosis. Neurobiol Aging 35:936.e1-4

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