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Dr. Dawson is collaborating with AGT to develop a gene therapeutic to arrest the development of Parkinson’s disease (PD) and other neurological disorders.
The main focus of the Dawson Laboratory at Johns Hopkins University is to unravel the molecular basis of neurodegeneration, which parallels Dr. Dawson’s clinical interest in neurodegenerative diseases.
The laboratory uses genetic, cell biological and biochemical approaches to explore the pathogenesis of Parkinson’s disease (PD) and other neurologic disorders. They also investigate 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.
There are five broad areas of investigation:
Dr. Dawson and his team originally identified NO as a major player in neuronal cell death, and they are investigating NO-death and NO-survival signaling pathways. They have shown that poly (ADP-ribose) polymerase (PARP) is a major target of NO-mediated neuronal injury and that selective inhibitors or knockout of PARP are profoundly neuroprotective in animal models of stroke and PD.
They recently identified 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. Current studies are focusing on the molecular mechanisms and identification of downstream targets of AIF’s actions and exploration of the role of other caspase-independent cell death effectors. The team is also investigating the mechanism by which PARP activation triggers AIF release and AIF kills cells.
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, we believe 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 a major focus of the Dawson Laboratory.
The team is studying the genetic basis of PD by investigating the mechanisms by which mutations in familial-linked genes cause PD. Mutations in a-synuclein or LRRK2 cause autosomal dominant PD, and mutations in parkin, PINK1 or DJ-1 cause autosomal recessive PD. The team found that parkin is an ubiquitin E3 protein ligase and that disease-causing mutations inhibit its E3 activity. They identified CDCrel-1 and synphilin-1 as parkin substrates and have shown that parkin’s E3 ligase activity may be important in the formation of Lewy bodies, the pathologic hallmark of PD. Mutations in parkin are a risk factor in sporadic PD. The team discovered that S-nitrosylation of parkin impairs its function. This discovery links the more common sporadic form of PD with alterations in parkin function. To assess the role of parkin, PINK1, and DJ-1 in PD pathogenesis in vivo, the team has knocked out DJ-1, PINK1, LRRK2 and parkin, and they are identifying and characterizing protein targets of parkin and the biologic function of LRRK2, DJ-1 and PINK1.
They are interested in genes essential for cell survival. To this end, they have been studying the role of NO as a survival molecule. Taking advantage of their findings that NO plays an important role in activity-dependent neuroprotection, they focused on identifying genes that are regulated by NO’s activation of Ras, and more than 30 candidate neuroprotective genes have been 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.
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