Dimitri Krainc, MD PhD

Dimitri Krainc, MD, PhD

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.

Dr. Krainc sees patients with movement and other neurological disorders at Massachusetts General Hospital in Boston.

Gene Transcription and Disease

Dr. Krainc's laboratory demonstrated that by targeting specific components of the transcription apparatus, mutant huntingtin leads to repression of gene transcription and consequently neuronal dysfunction, suggesting that an early step in the development of disease may involve deregulation of specific transcriptional programs. 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 recent initiative in Dr. Krainc's laboratory has been to define the autophagic-lysosomal pathways responsible for the clearance of mutant proteins causing Huntington's and Parkinson's disease. The 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 of this disease, and may contribute towards other neurodegenerative disorders which have mutant protein accumulation at their core.

Recent Publications

Dunah AW et al. Sp1 and TAF130 transcriptional activity disrupted in early Huntington's Disease. Science, 2002; 296, 2238.

Zhai W. et al. In vitroAnalysis of Huntingtin Mediated Transcriptional Repression Reveals Novel Target and Mechanism, Cell, 2005; 123, 1241-53.

Lin J. et al. Defects in adaptive energy metabolism with CNS-linked hyperactivity in PGC-1alpha null mice. Cell, 2004, 119:121-135.

Cui L. et al. Transcriptional Repression of PGC-1alpha by Mutant Huntingtin Leads to Mitochondrial Dysfunction and Neurodegeneration. Cell, 2006, 127, 59-69.

Borovecki F. et al. Genome-Wide Expression Profiling of Human Blood Reveals Biomarkers for Huntington's Disease. PNAS 2005; 102, 11023-8.