Recessive Neurodegenerative Disease


Biology of Batten Disease

The Davidson laboratory studies inherited genetic diseases that cause central nervous system dysfunction and gene therapy to the central nervous system. One form of Batten disease, a childhood onset neurodegerative disease, is due to a deficiency of a lysosomal protein, ceroid lipofuscinosis type III, or CLN3. We have showed that CLN3 is a lysosomal membrane protein and also how mutations within CLN3 alter protein trafficking and function. Using in vitro transcription and translation experiments, we have begun to unravel how the protein orientates itself within the lysosomal membrane. Additional experiments are underway to test if CLN3 associates with other lysosomal or non-lysosomal proteins. We have ongoing studies aimed at determing CLN3 function with in a cell. To approach these studies we generated a CLN3 animal model for further disease study and for studies to determine if gene transfer of CLN3 to the brain restores normal CLN3 activity and is able to reverse disease phenotypes.  The ultimate goal is to understand how an absence of CLN3 leads to neurodegeneration, and to test if gene replacement imparts protection to the diseaes phenotypes.

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References:

Sialic acid deposition impairs the utility of AAV9, but not peptide-modified AAVs for brain gene therapy in a mouse model of lysosomal storage disease. Chen YH, Claflin K, Geoghegan JC, Davidson BL. Mol Ther. 2012 Jul;20(7):1393-9. (Abstract)

Clarifying lysosomal storage diseases. Schultz ML, Tecedor L, Chang M, Davidson BL. Trends Neurosci. 2011 Aug;34(8):401-10. (Abstract)

A knock-in reporter mouse model for Batten disease reveals predominant expression of Cln3 in visual, limbic and subcortical motor structures. Ding SL, Tecedor L, Stein CS, Davidson BL. Neurobiol Dis. 2011 Feb;41(2):237-48. (Abstract)

Osmoregulation of ceroid neuronal lipofuscinosis type 3 in the renal medulla. Stein CS, Yancey PH, Martins I, Sigmund RD, Stokes JB, Davidson BL. Am J Physiol Cell Physiol. 2010 Jun;298(6):C1388-400. (Abstract)

Molecular signatures of disease brain endothelia provide new sites for CNS-directed enzyme therapy. Chen YH, Chang M, Davidson BL. Nat Med. 2009 Oct;15(10):1215-8. (Abstract)

Intraventricular enzyme replacement improves disease phenotypes in a mouse model of late infantile neuronal ceroid lipofuscinosis.  Chang M, Cooper JD, Sleat DE, Cheng SH, Dodge JC, Passini MA, Lobel P, Davidson BL.  Mol Ther. 2008 Apr;16(4):649-56. (Abstract) (pdf)

A knock-in reporter model of Batten disease. Eliason SL, Stein CS, Mao Q, Tecedor L, Ding SL, Gaines DM, Davidson BL. J Neurosci. 2007 Sep 12;27(37):9826-34. (Abstract)


 

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