Progress Towards Understanding the Molecular Basis of Parkinson's Disease

Progress Towards Understanding the Molecular Basis of Parkinson's Disease

Thursday, December 8, 2005

The New York Academy of Sciences

Presented By


The Neurodegenerative Diseases Discussion Group focuses broadly on the theme of neurodegenerative diseases in an interdisciplinary fashion. Meetings cover a single issue as it relates to neurodegenerative diseases in general, including cell death, mitochondrial function, protein misfolding, glial cell function, motor neuron deficiencies, and synaptic integrity. In addition, each meeting will feature talks covering basic, clinical, and translational aspects of research into neurodegenerative diseases.


Serge Przedborski, Center for Neurobiology and Behavior, Columbia University, "Parkinson's Disease: Mechanisms and Models."

David Eliezer, Weill Medical College of Cornell University, "Structural Properties and Interactions of the Parkinson's and Alzheimer's Proteins Synuclein and Tau."

Benoit Giasson, University of Pennsylvania, "Genetic and Molecular Effectors of Alpha-Synuclein Aggregation Involved in Parkinson's Disease."


"Parkinson's Disease: Mechanisms and Models"

Serge Przedborski
Parkinson's disease (PD) is the second most frequent neurodegenerative disorder after Alzheimer's disease. PD is essentially a sporadic condition whose etiology and pathogenesis both remain enigmatic. Thanks to pre-clinical findings yielded by both in vitro and in vivo experimental models of PD, most researchers now agree that the demise of dopaminergic neurons in sporadic PD results not from the action of a single deleterious factor, but rather from the concerted effects of multiple noxious factors. In looking at the long list of potential cellular and molecular culprits in the death of nigral dopaminergic neurons in PD, it appears that these factors can be divided into intrinsic, i.e. events occurring inside the dopaminergic neuron, and extrinsic, i.e. events occurring outside the dopaminergic neuron. Based on this view, the neurodegenerative process starts with otherwise healthy dopaminergic neurons being hit by an etiological factor, which then sets in motion a cascade of deleterious factors within that neuron. Investigations performed in the MPTP model of PD show that early molecular alterations in nigral dopaminergic neurons include inhibition of mitochondrial respiration, activation of the enzyme poly(ADP-ribose) polymerase, and increased formation of reactive oxygen species (ROS). Although the combination of energy crisis and oxidative stress likely kill some nigral dopaminergic neurons, most do not succumb to these early perturbations. Instead, they triggers other intracellular molecular pathways such as Jun N-terminal kinase (JNK), cyclooxygenase-2 (COX-2), and apoptosis. Only then, under the effects of these true cell executioners, are the dopaminergic neurons dying. While the dopaminergic neurodegenerative process evolves, alterations such as the glutamatergic input to the nigra grow, and indices of neuroinflammation develop. These changes do increase the amount of stress to which the neighboring compromised dopaminergic neurons are subjected, thereby amplifying the neurodegenerative process. This complex cascade of cellular and molecular events integrates many of the main discoveries accomplished over the past two decades. While primarily based on pre-clinical work, this pathogenic cascade has markedly influenced our understanding of PD pathogenesis and has provided a conceptual framework for novel therapies.

"Structural Properties and Interactions of the Parkinson's and Alzheimer's Proteins Synuclein and Tau"
David Eliezer
The protein alpha-synuclein, is genetically and histopathologically linked to the pathogenesis of Parkinson's disease, whereas the protein tau is similarly linked to Alzheimer's disease and a closely related dementia. Recent evidence suggests that interactions between these two proteins may also be important in neurodegenerative processes. We ha