Accumulation of misfolded proteins is a feature of aging and appears to be accelerated in many neurodegenerative disorders. Protein misfolding can result from defects in the chaperone system or may arise due to mutations or oxidative damage.  Recent data indicates that the misfolded proteins play an active role in cellular toxicity. The broad objective of these studies is to understand the mechanisms by which misfolded proteins perturb cellular homeostasis including protein expression and turnover, and energy metabolism. Because a stretch of more than 37 glutamines is known to misfold, accumulate in cells and induce toxicity, we use the expression of the expanded polyglutamine repeats devoid of the caspase cleavage sites in flanking sequences as one of the systems to study the mechanisms of proteotoxicity.

While an Instructor in Junying Yuan’s laboratory and with the help of Christian Mahlke, a talented technician, I showed that polyglutamine misfolding and caspase 8 activation play a critical role in cell death following expression of the expanded polyglutamine repeats. Unlike in the Fas pathway, the active caspase 8 is triggered by its recruitment to the misfolded polyglutamine proteins (Sanchez et. al., 1999). Moreover, oligomerization of the expanded repeats appears required for toxicity including metabolic inhibition and caspase activation as shown by FRET assays and the use of the oligomer compound inhibitor, congo red (Sanchez et. al., 2003).  Therefore, our working hypothesis is that small oligomeric forms of misfolded proteins assuming an amyloid-like conformation acquire the ability to interact with multiple signaling proteins underlying multiple of downstream toxic events. To identify and characterize signaling pathways and mediators linking misfolded proteins to cellular toxicity we are using functional proteomics, RNAi, and compounds identified by high-throughput screens against expanded polyglutamine induced ATP depletion and increased ROS levels.

Expanded Triplet Repeats and Disease:

Abnormal lengths of triplet repeats in otherwise non-related genes have been shown to underlie several CNS disorders. A recent project in the lab is focused on elucidating the role of triplet repeats in the regulation of the calcium activated potassium channel subunit, SK3, a protein found mutated in several cohorts of schizophrenia patients.

Glia-Neuron signaling:

Using optic nerves from developing and myelin mutant mice as model systems we and other investigators found that profound changes in the spatial organization, stability, ultrastructure, and site specific phosphorylation of the axonal cytoskeleton are induced by myelinating glia. We are interested in using molecular and chemical biology to identify the mediators and characterize the glia factors involved in axonal maturation. In addition, because some of these changes occur at the peak of developmental programmed cell death we are investigating the relationship between cell survival signals and neuronal differentiation.

Cytoskeleton and Signaling:

Although the expression of two kinase known to phosphorylate cytoskeleton proteins, cdk5 and erk kinase appears to be developmentally regulated, we and other laboratories found that their activity and distribution appears to be regulated by myelin-mediated extrinsic factors. Furthermore increased levels of cytoskeleton bound cdk5 kinase have been detected in affected tissue from Amyotrophic Lateral Sclerosis (ALS) patients and animal models and the cdk5 activator, p35 has been shown to play a critical role in Alzheimer’s disease. We are interested in understanding how the cytoskeleton contributes to the modulation of signaling pathways during differentiation and in pathological conditions.


Primary teaching affiliate
of BU School of Medicine