The Mechanisms of Neurodegeneration Laboratory, led by dr. Dimitri Krainc, focuses on using molecular and genomic approaches to identify common mechanisms that lead to neurodegeneration. Alzheimer’s, Parkinson’s, Amyotrophic Lateral Sclerosis, and Huntington’s disease (HD) presents with different symptoms but have related underlying mechanisms that lead to neuronal degeneration. Since HD is clinically and genetically the most defined among these disorders, we hypothesize that focusing on HD as a model system, the general mechanisms of neurodegeneration may be elucidated.
The projects described below are conducted in collaboration with Dr. Krainc’s laboratory at the Massachusetts General Hospital and Harvard Medical School in Boston (http://www.mghmind.org).
Gene Transcription and Disease
Dr. Krainc’s group demonstrated that targeting of specific components of the transcription apparatus by mutant huntingtin represents an early step in the development of HD. In order to identify biologically relevant targets of this transcriptional dysfunction, 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. Since energy metabolism plays a crucial role in normal neuronal functions, these findings may be applicable to other neurodegenerative disorders such as PD, ALS and AD.
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 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.
Biomarkers for Neurodegenerative Diseases
There are currently no effective neuroprotective treatments for diseases such as Parkinson’s disease, Alzheimer’s disease and Huntington’s disease. Therapeutic development is hindered by the inability to determine early indicators of efficacy in trials of new therapeutic compounds. Biomarkers assessing activity and progression of disease would greatly improve the therapeutic development process. A biomarker at its most simplistic is a biological characteristic that is objectively measured and evaluated as an indicator of normal biologic processes, pathogenic processes, or pharmacologic responses to a therapeutic intervention. Using genome- wide expression profiling, Dr. Krainc’s group focuses on development of biomarkers for Huntington’s and Parkinson’s Disease that distinguish these diseases from controls and correlate with disease stage and response to treatment. Dr. Krainc and his collaborators across Europe have been recently awarded a grant (Framework Program 6) to elucidate genomic biomarkers for genetic and sporadic PD. Such biomarkers may provide clues to disease pathogenesis and predict clinical benefit of new therapeutics in clinical trials.