The Role of Mitochondrial Dysfunction in Neurodegenerative Disorders

The Role of Mitochondrial Dysfunction in Neurodegenerative Disorders

Monday, May 22, 2006

The New York Academy of Sciences

Presented By

 

Organizers: Neil Upton and Isabel Gonzalez, GlaxoSmithKline

Program


5:00 pm - 7:30 pm: Presentations

David Nicholls
, Buck Institute for Age Research, "Mitochondrial Bioenergetics in Stressed Neurons."

Yadong Huang, University of California, San Francisco, "Apolipoprotein E Proteolysis: a Causative Factor and a Therapeutic Target in Alzheimer's Disease."

Lee Martin, Johns Hopkins University School of Medicine, "Mitochondrial Damage and Neuron Cell Death in Transgenic Mouse Models of Amyotrophic Lateral Sclerosis (ALS) and Parkinson's Disease (PD)."

Abstracts

"Mitochondrial Bioenergetics in Stressed Neurons"
David Nicholls
Recent technical advances have greatly facilitated the study of in situ mitochondrial bioenergetics in neuronal cell cultures. As a result, it is now possible to monitor mitochondrial respiration in coverslip attached neurons, while fluorescent imaging techniques to monitor mitochondrial and plasma membrane potentials and mitochondrial superoxide generation have also been refined. These techniques have been applied to the study of glutamate excitotoxicity, apoptosis, oxidative stress induced by glutathione depletion, and anoxia. Examples of the application of these techniques to transgenic neurodegenerative models will be discussed.

"Apolipoprotein E Proteolysis: a Causative Factor and a Therapeutic Target in Alzheimer's Disease"
Yadong Huang
ApoE4 has been genetically linked to late-onset familial and sporadic AD and has a gene-dose effect on the risk and age of onset of the disease. Recently, several hypotheses have been advanced to explain the association of apoE4 with AD, which suggests both Αβ–dependent and Αβ–independent roles of apoE4 in AD pathogenesis. Our studies have demonstrated a biological event that could play a major role in Αβ–independent apoE4-related neuropathology. Specifically, apoE is subject to cleavage by a neuron-specific chymotrypsin-like serine protease that generates bioactive carboxyl-terminal-truncated fragments of apoE. ApoE4 is more susceptible to this cleavage than apoE3, due to a unique intramolecular domain interaction in apoE4. These apoE fragments are found at higher levels in the brains of AD patients than in age- and sex-matched controls. In cultured neuronal cells, the truncated apoE4 escapes the secretory pathway, enters the cytosol, and interacts with cytoskeletal components and the mitochondria, leading to cytoskeletal disruption and mitochondrial dysfunction and ultimately cell death. Expression of the carboxyl-terminal-truncated apoE4 also causes AD-like neurodegeneration and behavioral deficits in transgenic mice. Importantly, apoE3 undergoes proteolytic cleavage, albeit less readily than apoE4. Thus, apoE fragments might also contribute to the development of AD in apoE3 carriers, which is consistent with the different effects of apoE3 and apoE4 on AD onset. Since apoE is synthesized by neurons under diverse pathophysiological conditions, this cleavage represents a causative factor in the pathogenesis of AD, and provide targets for anti-AD drug development, including suppression of neuronal production of apoE, inhibition of the apoE-cleaving enzyme, and blocking the interaction of apoE fragments with the cytoskeletal components and mitochondria