Spongiform neurodegeneration is a unique form of neurodegeneration characterized by vacuolation in neurons, neuronal cell death, and astrocytosis. Spongiform neurodegeneration is best known as the hallmark of prion disease, and this pathology is also present in the brains of patients suffering from Alzheimer's disease, diffuse Lewy body disease, and acquired immune deficiency syndrome (AIDS). The most common human prion disease is Creutzfeldt-Jakob disease (CJD), which occurs in sporadic, infectious, and inherited forms. The sporadic CJD form accounts for 85% of cases and is a late-onset (average age of onset = 60 years) neurodegenerative disorder of unknown cause. Although the prion protein has been extensively studied, the pathogenic mechanism underlying spongiform neurodegeneration remains elusive. Interestingly, a recent genetic study reveals that a null mutation in the gene encoding a novel protein called Mahogunin (Mgrn1) causes age-dependent, progressive spongiform neurodegeneration in mice that includes many features of prion disease but without accumulation of protease-resistant prion protein. At present, very little is known about the biological function of Mgrn1 and how loss of Mgrn1 function causes spongiform neurodegeneration. Mgrn1 contains a RING finger, a motif thought to be the key determinant of E3 ubiquitin-protein ligase activity. It has been speculated that loss of Mgrn1 function may cause spongiform neurodegeneration by impairing the ubiquitination and subsequent proteasomal degradation of yet-to-be-identified substrate(s) of Mgrn1. In contrast, the applicant's preliminary results have led to an intriguing hypothesis that Mgrn1 functions in a proteasome-independent, ubiquitin signalling pathway and suggest a novel mechanism by which defective ubiquitination may cause spongiform neurodegeneration. In this project, the applicant's group will follow up on these exciting results and use a combination of biochemical, cell biological, and molecular genetic approaches to investigate the cellular role of Mgrn1 E3 ligase, identify its substrates, and elucidate the molecular mechanism by which loss of Mgrn1 function causes age-dependent spongiform neurodegeneration. Completion of the proposed project should advance our understanding of the pathogenic mechanism underlying spongiform neurodegeneration and facilitate the development of new therapeutic strategies for treating age-related neurodegenerative disorders.

Public Health Relevance

Spongiform neurodegeneration is most commonly associated with prion disease, but also occurs in patients suffering from age-related neurodegenerative disorders, such as Alzheimer's disease and diffuse Lewy body disease. The goal of the proposed research is to define the molecular pathogenic mechanism that causes age-dependent spongiform neurodegeneration. The results of the proposed studies will provide fundamental information needed for the development of effective therapeutics to combat age-related neurodegenerative diseases.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Project (R01)
Project #
5R01AG034126-04
Application #
8308418
Study Section
Cellular and Molecular Biology of Neurodegeneration Study Section (CMND)
Program Officer
Wise, Bradley C
Project Start
2009-08-01
Project End
2014-07-31
Budget Start
2012-08-01
Budget End
2013-07-31
Support Year
4
Fiscal Year
2012
Total Cost
$302,368
Indirect Cost
$107,292
Name
Emory University
Department
Pharmacology
Type
Schools of Medicine
DUNS #
066469933
City
Atlanta
State
GA
Country
United States
Zip Code
30322
Yung, Cheryl; Sha, Di; Li, Lian et al. (2016) Parkin Protects Against Misfolded SOD1 Toxicity by Promoting Its Aggresome Formation and Autophagic Clearance. Mol Neurobiol 53:6270-6287
Fallaize, Dana; Chin, Lih-Shen; Li, Lian (2015) Differential submitochondrial localization of PINK1 as a molecular switch for mediating distinct mitochondrial signaling pathways. Cell Signal 27:2543-54
McKeon, Jeanne E; Sha, Di; Li, Lian et al. (2015) Parkin-mediated K63-polyubiquitination targets ubiquitin C-terminal hydrolase L1 for degradation by the autophagy-lysosome system. Cell Mol Life Sci 72:1811-24
Lee, Samuel M; Sha, Di; Mohammed, Anum A et al. (2013) Motor and sensory neuropathy due to myelin infolding and paranodal damage in a transgenic mouse model of Charcot-Marie-Tooth disease type 1C. Hum Mol Genet 22:1755-70
Chin, Lih-Shen; Lee, Samuel M; Li, Lian (2013) SIMPLE: A new regulator of endosomal trafficking and signaling in health and disease. Commun Integr Biol 6:e24214
Lee, Samuel M; Chin, Lih-Shen; Li, Lian (2012) Therapeutic implications of protein homeostasis in demyelinating peripheral neuropathies. Expert Rev Neurother 12:1041-3
Lee, Samuel M; Chin, Lih-Shen; Li, Lian (2012) Protein misfolding and clearance in demyelinating peripheral neuropathies: Therapeutic implications. Commun Integr Biol 5:107-10
Lee, Samuel M; Chin, Lih-Shen; Li, Lian (2012) Charcot-Marie-Tooth disease-linked protein SIMPLE functions with the ESCRT machinery in endosomal trafficking. J Cell Biol 199:799-816
Hurst-Kennedy, Jennifer; Chin, Lih-Shen; Li, Lian (2012) Ubiquitin C-terminal hydrolase l1 in tumorigenesis. Biochem Res Int 2012:123706
Lee, Samuel M; Olzmann, James A; Chin, Lih-Shen et al. (2011) Mutations associated with Charcot-Marie-Tooth disease cause SIMPLE protein mislocalization and degradation by the proteasome and aggresome-autophagy pathways. J Cell Sci 124:3319-31

Showing the most recent 10 out of 13 publications