UMMS Affiliation

Department of Neurology; Department of Medicine, Division of Endocrinology and Metabolism; Horae Gene Therapy Center

Publication Date


Document Type



Cell Biology | Genetics and Genomics | Nervous System Diseases | Neurology


BACKGROUND: Mutant huntingtin (mHTT) is encoded by the Huntington's disease (HD) gene and its accumulation in the brain contributes to HD pathogenesis. Reducing mHTT levels through activation of the autophagosome-lysosomal pathway may have therapeutic benefit. Transcription factor EB (TFEB) regulates lysosome biogenesis and autophagy.

OBJECTIVE: To examine if increasing TFEB protein levels in HD mouse striatum induces autophagy and influences mHTT levels.

METHODS: We introduced cDNA encoding TFEB with an HA tag (TFEB-HA) under the control of neuron specific synapsin 1 promoter into the striatum of 3 month old HDQ175/Q7 mice using adeno-associated virus AAV2/9. The levels of exogenous TFEB were analyzed using qPCR and Western blot. Proteins involved in autophagy, levels of huntingtin, and striatal-enriched proteins were examined using biochemical and/or immunohistochemical methods.

RESULTS: In HD mice expressing TFEB-HA, HA immunoreactivity distributed throughout the striatum in neuronal cell bodies and processes and preferentially in neuronal nuclei and overlapped with a loss of DARPP32 immunoreactivity. TFEB-HA mRNA and protein were detected in striatal lysates. There were increased levels of proteins involved with autophagosome/lysosome activity including LAMP-2A, LC3II, and cathepsin D and reduced levels of mutant HTT and the striatal enriched proteins DARPP32 and PDE10A. Compared to WT mice, HDQ175/Q7 mice had elevated levels of the ER stress protein GRP78/BiP and with TFEB-HA expression, increased levels of the astrocyte marker GFAP and pro-caspase 3.

CONCLUSION: These results suggest that TFEB expression in the striatum of HDQ175/Q7 mice stimulates autophagy and lysosome activity, and lowers mHTT, but may also increase a neuronal stress response.


Adeno associated virus, GRP78/BiP, Huntington’s disease, LC3, TFEB, autophagy, huntingtin, neurodegeneration, striatum

DOI of Published Version



J Huntingtons Dis. 2016 Oct 1;5(3):249-260. Link to article on publisher's site

Journal/Book/Conference Title

Journal of Huntington's disease

Related Resources

Link to Article in PubMed

PubMed ID


Creative Commons License

Creative Commons Attribution-Noncommercial 4.0 License
This work is licensed under a Creative Commons Attribution-Noncommercial 4.0 License



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