Dr. Masliah has held a joint appointment in Neurosciences and Pathology since 1992. He heads the Experimental Neuropathology Laboratory, which engages foremost in the scientific pursuit of the cellular and molecular mechanisms leading to synaptic damage in neurodegenerative disorders such as Alzheimer's disease (AD), Parkinson's disease (PD), and the dementia associated with AIDS. The laboratory continues to make progress in elucidating the mechanisms by which abnormal protein folding leads to neurodegeneration. This information has fostered the development of new transgenic animal models that are being utilized to test compounds that will ameliorate the neurodegenerative process by decreasing protein oligomerization. The main hypothesis of this research is that during neurodegeneration there is an abnormal accumulation of synaptic proteins with amyloidogenic potential at the synaptic terminal, and that these abnormally aggregated proteins become neurotoxic and interfere with synaptic function.
Currently, the research efforts of the Masliah Laboratory are directed toward understanding the mechanisms by which abnormal a-synuclein aggregation leads to neurodegeneration in AD and PD. This research is an outgrowth of the discovery of a mutation in this gene leading to familial PD. The Masliah lab has a long track record of investigating a-synuclein, after cloning the human homologue of a-synuclein and observing that this molecule abnormally accumulates in the plaques and synapses of patients with AD and in the Lewy bodies of PD patients. The group is recognized for having developed the first transgenic mouse model as well as an in vitro model system suggesting that oxidative stress might play an important role by promoting abnormal aggregation of a-synuclein.
The Masliah lab group has made two fundamentally new discoveries associated with the role of a-synuclein in the pathogenesis of neurodegeneration. First, they found that Ab1-42 actually promotes a-synuclein aggregation. This is important because it explains why a large proportion of patients with AD develop parkinsonism and why there is considerable overlap between AD and PD. Second, they found, for the first time, an endogenous molecule with the capacity of binding a-synuclein and preventing or decreasing the neurotoxic conversion of this molecule. This molecule is a close homologue to a-synuclein and was named a-synuclein. The team has developed compounds mimicking a-synuclein as well as viral vectors expressing this gene and has been testing them in models of AD and PD in an effort to develop novel gene therapies for these disorders.
These studies have now been extended to identify other factors promoting and preventing a-synuclein aggregation along a pathogenic spectrum extending from oligomerization (protofibril) formation to polymerization (fibril formation). These pathways have been found to converge on the JNK-JIP1 signaling pathway, triggering or blocking neurodegeneration. The group has described these studies in numerous articles published in Nature, Science, Proceedings of the National Academy of Sciences, Neuron, and Journal of Neuroscience.
The work of the Masliah group has generated interest from both the neurosciences community and the pharmaceutical industry. Research activities are supported through substantial federal funding as well as through an award from the Michael J. Fox Foundation.
In February 2007, following the death of Clifford Shults, MD, who was Principal Investigator of the NINDS P01 grant Pathogenesis and Diagnosis of Multiple System Atrophy (MSA), Dr. Masliah agreed to oversee and continue Dr. Shults's work on pathogenic factors for MSA, particularly the role played by alpha-synuclein, and on evaluation of clinical and laboratory assessments used to diagnose and follow the course of the illness. In addition to the Shults laboratory team, Dr. Masliah is supported in this effort by biostatisticians Susanne J. May, PhD, and Ronald Thomas, PhD.
The Masliah laboratory also continues to make strides in studies of the mechanisms by which human immunodeficiency virus (HIV) might trigger neurodegeneration and cognitive impairment. Specifically, their efforts are focused on understanding the role of HIV-related receptors in mediating neurodegeneration. The group found that FGF1 is capable of preventing the toxic effects of HIV proteins by modulating the expression of HIV-related receptors and blocking the GSK3b pathway via Akt activation. They have been able to develop new experimental tg models and have identified compounds that block the GSK3b pathway and decrease the HIV neurotoxicity. NIMH has provided funding to establish a NeuroAIDS tissue network.
Dr. Masliah is committed to training a new generation of students in the area of novel biomedical techniques to evaluate synaptic organization in the brain. In his capacity as Director of the Pathology Service, he is actively involved in the training of pathology residents and has completely rewritten the Autopsy Manual for resident training.
Dr. Masliah serves on the Editorial Boards of the Journal of Neuropathology, Journal of Experimental Neurology, and Journal of Laboratory Investigation. He regularly reviews manuscripts for a number of journals, including Proceedings of the National Academy of Sciences, Journal of Clinical Investigation, and Journal of Neurosciences. He also serves as a member of the NIA Neuroscience of Aging Study section. He has presented his research at numerous conferences, meetings, and symposia at the national and international levels.