Massachusetts General Hospital

Biography

Dr. Krainc is an Associate Professor of Neurology at Harvard Medical School and a Neurologist at the Massachusetts General Hospital. He directs a research laboratory at the MassGeneral Institute for Neurodegenerative Disorders (MIND). His group studies disease mechanisms such as mitochondrial dysfunction and protein accumulation that are applicable to various neurodegenerative disorders, including Parkinson's disease. Dr. Krainc's group recently identified a novel mechanism of autophagic-lysosomal degradation that promotes selective clearance of mutant huntingtin. His lab also studies lysosomal function in Gaucher disease, lysosomal storage disorder that is clinically linked to PD. The more recent initiative in Dr. Krainc's laboratory has been to develop human neuronal models by reprogramming skin fibroblast (iPS) obtained from patients with genetic and sporadic PD. His lab studies mitochondrial function in iPS neurons and participates in NIH supported PD Consortium to develop and characterize iPS-derived dopaminergic neurons.

Research

Gene Transcription and Disease
Dimitri Krainc, MD PhD is using molecular and genomic approaches to identify mechanisms that lead to neurodegeneration. In particular, his research interest involves deciphering the molecular pathways of transcriptional deregulation and mutant protein accumulation in Huntington's disease (HD) and related neurodegenerative disorders.   In order to identify biologically relevant targets of this transcriptional dysfunction in HD, Dr. Krainc's group showed that huntingtin inhibits gene expression of PGC-1alpha, a transcriptional coactivator that regulates several metabolic processes including mitochondrial biogenesis and respiration.  These studies demonstrated that deregulation of transcription by mutant huntingtin leads to defects in energy metabolism and dysfunction of neurons that are most vulnerable to metabolic stress in HD.  In an effort to help develop new therapies, Dr. Krainc's group conducts studies to correct these transcriptional and metabolic abnormalities in HD and related neurodegenerative disorders.

Clearance of Disease Proteins
A recurrent observation of accumulation and aggregation of mutant proteins in different neurodegenerative disorders indicates the possibility of a shared clearance mechanism.  Dr. Krainc's group identified a novel mechanism of autophagic-lysosomal degradation that promotes selective clearance of the mutant huntingtin protein.   Finding the modifiers of these pathways will identify needed targets for treatment.   

Publications

View my most recent publications at PubMed

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 Huntingtons 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.: Gauche?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)

updated 6/25/2012

2013 MGH Research Scholars

ESTABLISHED IN 2011 by ECOR and the MGH Research Advisory Council, the MGH Research Scholars program provides five years of unrestricted funding to give innovative investigators the flexibility to pursue projects that may lead in unexpected directions. Supported by philanthropic gifts, the program expanded from the first group of five recipients to eight scholars in 2012.

E Pluribus Unum for Parkinson Disease - Researchers Draw on Sources to Improve Treatment of PD

What do Gaucher’s disease, gout, and amyloid plaques have in common? For researchers at the MGH, each of them may shed light on the causes and treatment of Parkinson’s disease.

Rare genetic disorder provides unique insight into Parkinson’s disease

MGH investigators may have found the mechanism behind a previously reported link between the rare genetic condition Gaucher disease and the common neurodegenerative disorder Parkinson's disease.

Increased expression of regulatory enzyme may protect against neurodegeneration in Huntington's disease

Treatment that increases brain levels of an important regulatory enzyme may slow the loss of brain cells that characterizes Huntington's disease and other neurodegenerative disorders.