Massachusetts General Hospital

Overview

The overarching goal of Krainc laboratory has been to define key molecular pathways in the pathogenesis of neurodegeneration.  They have focused on pathogenic mechanisms that are commonly altered in neurodegenerative disorders such as deficient degradation of aggregation-prone proteins and mitochondrial dysfunction.  As a general strategy, they study rare genetic diseases with mutations in genes that play a role in these key mechanisms and pathways.  Models of Huntington’s, Parkinson’s and Gaucher disease have been utilized to examine if activation of cellular degradation pathways and/or modifications of mutant proteins can lead to protection in these disorders. 

Their results suggest that modest upregulation of baseline autophagic and lysosomal degradation coupled with specific posttranslational modifications of mutant proteins improves the overall capacity of cells to properly dispose toxic proteins.  To validate and study these findings in human neurons, they have employed induced pluripotent stem cells (iPS) generated by reprogramming of patient-specific skin fibroblasts. These iPS cells are differentiated into specific neuronal subtypes in order to study disease mechanisms and to test candidate therapies.

Updated 1/18/2012

Principal Investigator

Dimitri Krainc, MD, PhD

• Associate Professor,
  Harvard Medical School
• Associate Neurologist,
  Massachusetts General Hospital

Lab Members

John Graziotto	Hyun Jeong	Joseph Mazzulli	Isabella Palazzolo
Jessica Sadick	Philip Seibler	Maria Usenovic	Min Xiang

Updated 1/18/2012

Research Projects

The overarching goal of Krainc laboratory has been to define key molecular pathways in the pathogenesis of neurodegeneration.  They have focused on pathogenic mechanisms that are commonly altered in neurodegenerative disorders such as deficient degradation of aggregation-prone proteins and mitochondrial dysfunction.  As a general strategy, they study rare genetic diseases with mutations in genes that play a role in these key mechanisms and pathways.  Models of Huntington’s, Parkinson’s and Gaucher disease have been utilized to examine if activation of cellular degradation pathways and/or modifications of mutant proteins can lead to protection in these disorders. 

Their results suggest that modest upregulation of baseline autophagic and lysosomal degradation coupled with specific posttranslational modifications of mutant proteins improves the overall capacity of cells to properly dispose toxic proteins.  To validate and study these findings in human neurons, they have employed induced pluripotent stem cells (iPS) generated by reprogramming of patient-specific skin fibroblasts. These iPS cells are differentiated into specific neuronal subtypes in order to study disease mechanisms and to test candidate therapies.

	While these studies suggested that the soluble mutant protein represents the toxic moiety, aggregation of mutant proteins serves as a marker of inefficient degradation in neurodegenerative disorders and other proteinopathies.  Models of HD, Parkinson’s disease, Gaucher disease and Hutchinson-Gilford Progeria have been utilized to examine if activation of cellular degradation pathways and/or modifications of mutant proteins can lead to protection in these disorders.  In HD, modification of mutant huntingtin by acetylation resulted in more efficient degradation of the mutant protein by autophagic/lysosomal degradation pathways (Jeong et al, Cell, 2009), suggesting that novel therapeutic agents that promote acetylation and degradation of the mutant protein could provide beneficial in HD. Studies of Hutchinson-Gilford progeria suggested that general upregulation of autophagic/lysosomal pathway dramatically reversed the pathologic phenotype in patient cells (Cao et al, Science Translational Medicine, 2011).
	The importance of autophagic/lysosomal pathways in neurodegeneration has been further highlighted by a link between lysosomal storage disorder, Gaucher disease (GD) and PD.  GD patients and their relatives have increased risk for PD, and people with PD or idiopathic parkinsonism are more likely to carry glucocerebrosidase gene (GBA) mutations that cause Gaucher’s.  The drop in lysosomal GBA causes a buildup of glucosylceramide, which stabilizes toxic alpha-synuclein oligomers. On the other hand, the accumulation of alpha-synuclein further inhibits trafficking of GBA from ER to Golgi, leading to a positive feedback loop between alpha-synuclein and glucocerebrosidase that could lead to a self-propagating disease (Mazzulli et al, Cell, 2011).  These data suggested that improved targeting of glucocerebrosidase to lysosomes could represent a specific therapeutic target for PD and other synucleinopathies.
	Ongoing projects in the lab are further delineating the connection between lysosomal dysfunction and neurodegeneration, by examining mechanistically how other lysosomal storage disorders lead to neurodegeneration and accumulation of disease-linked proteins.http://pdips.org), novel technologies have been developed to further characterize the contribution of genetic, epigenetic and environmental factors to distinct neuronal phenotypes in iPS neurons and their relevance for therapeutic development in Parkinson’s and related disorders.   To validate and study these findings in human neurons, induced pluripotent stem cells (iPS) generated by reprogramming of patient-specific skin fibroblasts have been utilized. These iPS cells are differentiated into specific neuronal subtypes in order to study converging pathways of mitochondrial and lysosomal dysfunction in Parkinson’s disease and related neurodegenerative disorders (Seibler et al, J. Neuroscience, 2011; Mazzulli et al, Cell, 2011).   In collaboration with the PD iPS Consortium (http://pdips.org), novel technologies have been developed to further characterize the contribution of genetic, epigenetic and environmental factors to distinct neuronal phenotypes in iPS neurons and their relevance for therapeutic development in Parkinson’s and related disorders.

Updated 1/18/2012

Read about, and apply for residency, fellowship, and observership programs at http://www.massgeneral.org/neurology/education/.

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NCBI PubMed Publications

1. 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
2. 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.
3. 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
4. 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, 1-16.
5. 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)