Molecular and Cellular Signals Controlling Neurodegeneration, Neuronal Survival and Cell Death

The Dawson laboratory uses genetic, cell biological and biochemical approaches to explore the pathogenesis of Parkinson’s disease (PD) and other neurologic disorders.  The Lab also investigates several discrete mechanisms involved in cell death including the role of nitric oxide as an endogenous messenger, the function of poly (ADP-ribose) polymerase-1 and apoptosis inducing factor in cell death, and how endogenous cell survival mechanisms protect neurons from death. 

PD is a common disorder of the nervous system that afflicts patients later in life with tremor, slowness of movement, gait instability, and rigidity.  Loss of dopamine neurons accounts for the major signs and symptoms of PD and mutations in at least five genes including a-synuclein, parkin, PINK1, DJ-1 and LRRK2 are responsible for rare Mendelian forms of PD.  In addition to the progressive loss of dopamine neurons, PD is characterized by neurodegeneration throughout the central nervous system and by the accumulation of a-synuclein and other proteins in structures called Lewy bodies and Lewy neurites.  Despite genetic advances in our understanding of PD, it is primarily considered a sporadic disorder with no known cause.  Current evidence suggests that mitochondrial complex I abnormalities may be one of the major contributors to sporadic PD.  Much as the discovery of dopamine deficiency led to potent treatments for motor symptoms, the Dawson Lab believes that recent discoveries concerning the role of specific genes in Parkinson disease pathology will lead to the next revolution in disease therapy.  Accordingly, the role of these genes in the pathogenesis of PD; and how mitochondrial complex I deficiency potentially leads to pathologic derangements in the function of these proteins has become one of the laboratory’s major focus. 

The Lab originally identified NO as a major player in neuronal cell death and we are investigating NO-death and NO-survival signaling pathways. It showed that poly (ADP-ribose) polymerase (PARP) is a major target of NO mediated neuronal injury and showed that selective inhibitors or knockout of PARP are profoundly neuroprotective in animal models of stroke and PD. The Lab recently discovered a novel caspase-independent pathway of programmed cell death and showed that apoptosis inducing factor (AIF) is a critical cell death effector that acts downstream of NO/PARP. Moreover, it discovered that poly (ADP-ribose) (PAR) polymer, the biproduct of PARP activation is a novel cell death signaling molecule that plays a critical role in neuronal injury.  Current studies are focusing on the molecular mechanisms and identification of downstream targets of PAR polymer and AIF.

Given the Lab's interest in cell death, it is no surprise that it is interested in genes essential for cell survival.  To this end, the Dawson Lab has been studying the role of NO as a survival molecule. Taking advantage of its findings that NO plays an important role in activity-dependent neuroprotection, the Lab focused on identifying genes that are regulated by NO’s activation of Ras and over 30 candidate neuroprotective genes were identified.  Understanding the mechanism by which these proteins regulate neuronal survival may lead to the identification of innovative therapies for the treatment of neurologic disorders.

Source:  http://neuroscience.jhu.edu/resources/directory/faculty/Ted-Dawson