The most common neurodegenerative diseases, including Alzheimer’s, Parkinson’s, and Huntington’s diseases, each display distinct clinical presentations.   The basis of these distinct clinical presentations is enhanced vulnerability of certain neuronal types to death or dysfunction.   The Heiman Laboratory is broadly interested in this phenomenology of enhanced vulnerability in neurodegenerative disease, and view it as an opportunity to discover valuable insights into the cell biology of each disease-relevant neuronal cell type, as well as to identify new therapeutic targets.  We use innovative approaches to address these long-standing questions of selective vulnerability that have remained open questions in the field for decades.

The mammalian brain is composed of myriad cell types integrated into complex circuits.   Complexity at the cellular level has historically hampered molecular studies of the mammalian nervous system.   To help overcome this complexity and study the molecular profiles of distinct CNS cell types in situ, our lab makes use of the Translating Ribosome Affinity Purification (TRAP) methodology.   TRAP combines cell type-specific expression of transgenic proteins in genetically defined cell types with biochemical purification of translating ribosomes and their associated mRNAs.   We use TRAP and in vivo genetic screening methods to study the molecular mechanisms underlying various CNS degenerative diseases.   One of the diseases that we study is Huntington’s disease (HD), a monogenic neurodegenerative disease caused by mutations in the Huntingtin gene.   In HD, medium-sized spiny neurons (MSNs) of the striatum are earliest and most dramatically affected, while many other cell types are much less affected.   Through our TRAP and genetic screening studies, we have recently identified genes that either enhance or suppress mutant Huntingtin toxicity in MSNs, and hope to use this knowledge to identify new therapeutic targets for HD.