Burbulla, L.F., Song, P., Mazzulli, J.R., Zampese, E., Wong, Y.C., Jeon, S., Santos, D.P., Blanz, J., Obermaier, C., Strojny, C., Savas, J., Kiskinis, E., Zhuang, X., Krüger, R., Surmeier, J.D., Krainc, D. Dopamine oxidation mediates mitochondrial and lysosomal dysfunction in Parkinson's disease. Science, 2017; DOI: 10.1126/science.aam9080
Trajkovic, K., Jeong, H. and Krainc, D. “Mutant huntingtin is secreted via a late endosomal/lysosomal unconventional secretory pathway.” Journal of Neuroscience, 2017 Sep 13;37(37):9000-9012. doi: 10.1523/JNEUROSCI.0118-17
Wong, Y.C., and Krainc, D. “α-synuclein toxicity in neurodegeneration and therapeutic strategies.” Nature Medicine, 2016. 23, 1–13. doi:10.1038/nm.4269
Mazzulli J.R., Zunke, F., Tsunemi, T., Toker, N.J., Jeon, S., Burbulla, L.F., Patnaik, S, Ellen Sidransky, E., Marugan, J., Sue, C., and Krainc, D. Activation of β-Glucocerebrosidase Reduces Pathological α-Synuclein and Restores Lysosomal Function in Parkinson's Patient Midbrain Neurons. Journal of Neuroscience, 2016 Jul 20; 36(29): 7693–7706. doi: 10.1523/JNEUROSCI.0628-16.2016
Zheng, J., Chen, L., Silverman, R.B., Krainc, D. Design and Synthesis of Potent Quinazolines as Selective Glucocerebrosidase Modulators. J Med Chem, 2016,
Tsunemi T, Hamada K, Krainc D. ATP13A2/PARK9 Regulates Secretion of Exosomes and α-Synuclein. J Neurosci, 2014 Nov 12;34(46):15281-7. doi: 10.1523/JNEUROSCI.1629-14.2014.
Tsunemi, T and Krainc, D. Zn2+ dyshomeostasis caused by loss of ATP13A2/PARK9 leads to lysosomal dysfunction and alpha-synuclein accumulation. Human Molecular Genetics, 2014 Jun 1;23(11):2791-801
Tsunemi T, Ashe TD, Morrison BE, Soriano KR, Au J, Roque RA, Lazarowski ER, Damian VA, Masliah E, La Spada AR. PGC-1α rescues Huntington's disease proteotoxicity by preventing oxidative stress and promoting TFEB function. Sci Transl Med, 2012 Jul 11;4(142):142ra97.
Usenovic, M, Tresse. E., Mazzulli, J.R., Taylor J.P. and Krainc, D. Deficiency of ATP13A2 leads to lysosomal dysfunction, α-synuclein accumulation and neurotoxicity. J. Neurosci, 2012, 21;32:4240-6.
Usenovic, M., Knight, A.L., Ray, A., Wong, V., Brown, K.R., Caldwell, G. A., Caldwell, K.A, Stagljar I. and Krainc, D. Identification of novel ATP13A2 interactors and their role in α-synuclein misfolding and toxicity. Human Molecular Genetics, 2012; doi: 10.1093/hmg/dds206.
Mazzulli, J.R., Sun, Y., Knight, A.L., McLean, P.J., Caldwell, G, Sidransky, E, Grabowski, G.A. and Krainc, D. Gaucher’s Disease Glucocerebrosidase and alpha-synuclein form a bidirectional pathogenic loop in synucleinopathies. Cell, 2011; 146 (Perspectives in Cell, Science Translational Medicine, and Editors’ Choice in Science).
We found that inactive glucocerebrosidase leads to accumulation of the sphingolipid glucosylceramide in neurons. This accumulation of glucosylceramide leads to stabilization of toxic a-syn oligomers. We made a surprising observation that accumulation of a-syn can lead to inhibition of normal (not mutated) glucocerebrosidase. Specifically, a-syn interferes with ER to Golgi trafficking of glucocereberosidase which in turn leads to decreased glucocerebrosidase activity and more accumulation of a-syn. The bidirectional effects of a-syn and glucocerebrosidase forms a positive feedback loop that, after a threshold, leads to self propagating disease. This study also identifies a specific target (GCase) for therapeutic development in PD and other synucleinopathies and also highlights the importance of rare diseases for our understanding of more common conditions.
Seibler, P., Graziotto,J., Jeong, H., Simunovic F., Klein, C. and Krainc, D. Mitochondrial Parkin recruitment is impaired in neurons derived from mutant PINK1 iPS cells. J. Neurosci, 2011, 31, 5970.
Xiang Z, Valenza M., Cui L., Leoni V., Jeong H, Brilli E., Zhang J, Duan W., Reeves S.A., Cattaneo E. and Krainc D. PGC1a contributes to dysmyelination in experimental models of Huntington’s disease. J. Neurosci, 2011, 31(26):9544-9553.
Jeong, H., Cohen, D.E., Cui, L.; Supinski, A; Bordone, L; , Guarente, L.P, and Krainc, D. Sirt1 mediates neuroprotection from mutant huntingtin by activation of TORC1 and CREB transcriptional pathway. Nature Medicine, (advance online publication, December 2011, doi:10.1038/nm.2558). (Perspective in Nature Medicine and Nature Reviews Neuroscience).
We examined the normal function of Sirt1 in neurons and found that Sirt1 positively regulates CREB transcription by activating TORC1, brain-specific transcriptional coactivator of CREB. Sirt1-mediated increase in nuclear TORC1 results in enhanced interaction of TORC1 with CREB and activation of CREB target genes. We showed that Sirt1 regulates cAMP-mediated TORC1 activity and participates in the activity-dependent transcriptional regulation in the brain. While we found that overexpression of Sirt1 did not extend survival in normal mice, increased survival and neuroprotection was seen in HD-like mice, suggesting that Sirt1 activation becomes important under conditions of neuronal stress. We showed that mutant huntingtin inhibits TORC1 activation which leads to repression of CREB-regulated genes such BDNF and PGC-1alpha. Since TORC1 expression is essentially brain-specific, it represents an exciting target of Sirt1 function in neurons.
Cao, K*., Graziotto, J.J*, Blair, C.D, Mazzulli, J.R., Erdos, M.R., Krainc, D*. and Collins, F.S.*. Rapamycin reverses cellular phenotype and enhances mutant protein clearance in Hutchinson Gilford progeria syndrome. Science Translational Medicine, 2011, Jun 29;3(89) (*co-senior authors).
Jeong H., Then F., Mazzulli JR., Melia, T. Savas J., Voisine C., Tanese, N., Hart C.A., Yamamoto A. and Krainc D. Acetylation targets mutant huntingtin to autophagosomes for degradation. Cell, 2009; 137, 1-13. (Editors’s Choice, Science).
We showed that posttranslational modification of mutant huntingtin by acetylation facilitates trafficking of the mutant protein into autophagosomes for degradation by lysosomes. Enhanced clearance of mutant huntingtin rescues cells from the toxic effects of protein accumulation and can partially prevent neurodegeneration. This work identified protein acetylation as a signal for autophagic degradation and provided a foundation for studies by other groups that highlighted the role acetylation in protein degradation.
Cui L., Jeong H., Borovecki F. Parkhurst C., Tanese, N. and Krainc D. Transcriptional Repression of PGC-1alpha by Mutant Huntingtin Leads to Mitochondrial Dysfunction and Neurodegeneration. Cell, 2006; 126, 59-69. (Perspectives in Cell and Nature Medicine).
We used unbiased approaches to identify PGC-1alpha, a master regulator of mitochondrial function, as an important pathogenic target in HD. These studies identified a molecular link between transcriptional deregulation and mitochondrial dysfunction in HD. Several studies by other groups further highlighted the role of PGC-1alpha in HD and other neurodegenerative disorders.
Zhai, Jeong H., Cui L, Krainc D*, and Tjian R*. In vitro Analysis of Huntingtin Mediated Transcriptional Repression Reveals Novel Target and Mechanism. Cell, 2005; 123, 1241-53 (*co-senior authors).
Dunah AW, Jeong H., Griffin A., Kim MJ, Standaert DG, Hersch SM, Mouradian MM, Young AB, Tanese N. and Krainc D. Sp1 and TAF130 transcriptional activity disrupted in early Huntington’s Disease. Science, 2002; 296, 2238. (Perspective in Science).
We found that the glutamine expansion in huntingtin disrupts specific transcriptional programs in neurons. We then confirmed these results and also demonstrated (in collaboration with Tjian lab) that specific components (TFIID and TFIIF) of the general transcriptional machinery are directly targeted by mutant huntingtin (Zhai et al, Cell, 2004). These data suggested that the deregulated gene expression may be an early step in HD pathogenesis as a result of interference by the soluble forms of mutant huntingtin. Our work also indicated that one of the primary and direct effects of mutant huntingtin on transcription is via specific repressor mechanisms, whereas other effects of huntingtin on transcription may be compensatory or secondary.