Asa Abeliovich, MD, PhD

Research Summary
Molecular mechanisms of neurodegeneration and the life cycle of dopamine neurons.

We are studying the molecular bases of midbrain dopamine neuron development, function and survival. Midbrain dopamine neurons are thought to play key roles in learned and addictive behaviors, and degeneration of these neurons underlies Parkinson's disease.

A focus of the lab is to understand the mechanisms by which mutations in Parkinson’s disease-related genes, such as a-synuclein and parkin, lead to midbrain dopamine neuron dysfunction and eventual demise. We are also particularly interested in the normal cellular roles of these genes. We use a combination of molecular biological, cellular, and mouse genetic approaches to this end.

In a second project, we are characterizing molecules that play a important roles in the specification and late development of dopamine neurons using an in vitro culture system. Embryonic stem cells have been shown to give rise to dopamine neurons in response to a set of extrinsic cues such as sonic hedgehog and FGF8. Furthermore, a few intrinsic cellular factors, such as nurr1, have been implicated in the generation of dopamine neurons. We are using molecular biological tools to investigate the mechanism by which such intrinsic signals determine midbrain dopamine neuron fate.

Abeliovich, A., Schmitz, Y., Farinas, I., Choi-Lundberg, D., Ho, W.-H., Verdugo, J. M. G., Armanini, M., Ryan, A., Hynes, M., Phillips, H., Sulzer, D., and Rosenthal, A. (1999). Mice lacking a-synuclein display functional deficits in the nigrostriatal dopamine system. Neuron 25, 239-252.

Staropoli, J. F., McDermott, C., Martinat, C., Schulman, B., Demireva, E, and Abeliovich, A. (2003). Parkin is a Component of an SCF-like Ubiquitin Ligase Complex and Protects Postmitotic Neurons from Kainate Excitotoxicity. Neuron 37: 735-749.

1. Molecular Mechanisms of the Parkinson's disease genes
Mutations in the amino-terminal repeat domain of a-Synuclein (alpha-Syn) underlie rare autosomal-dominant, familial forms of PD. Familial, autosomal-recessive mutations in Parkin lead to both juvenile and adult-onset forms of PD. Furthermore, Parkin appears to possess a ubiquitin-ligase activity, implicating it in the protein degradation process. Both pathological and genetic data link altered protein degradation pathways with PD. A pathological hallmark of PD, the Lewy Body (LB), appears to represent intracellular inclusions composed of multiple proteins including ubiquitin, a-Synuclein (alpha-Syn), ubiquitin carboxy-terminal hydrolase (UCH-L1), and Parkin. Both Parkin and UCH-L1 are implicated in protein ubiquitination, whereas alpha-Syn appears to be a substrate of ubiquitination. The goal of this proposal is to gain an understanding of the mechanisms of action of the PD-related genes alpha-Syn, Parkin. Of particular interest are potential relationships among these molecules. I propose to combine complementary biochemical, cellular, and genetic approaches to this end.
National Institute on Aging
7/1/03-6/30/08

2. Molecular and Cellular Analyses of Parkin Function
Mutations in Parkin, a putative ubiquitin ligase component, cause a familial, autosomal recessive form of PD characterized by midbrain dopamine neuron loss. We propose to use molecular and cellular tools to investigate the mechanism of Parkin action in protein ubiquitination and neuronal survival. Our preliminary data indicate that Parkin associates in a multiprotein ubiquitin ligase complex with 2 previously characterized ubiquitin ligase components, the F-box/WD repeat-containing protein hSel- 10, and Cullin-1 (Cul 1). Furthermore, hSel-10 serves to direct this complex to specific substrates including Cyclin E, a putative regulator of neuronal apoptosis. We will test the hypotheses that (1) auxiliary components of the Parkin ubiquitin ligase complex serve to regulate or target this activity, and (2) that, in Parkin-associated familial PD, premature neuronal death is a consequence of defective ubiquitination and the accumulation of neuronal apoptosis-related Parkin complex substrates.
National Institute of Neurological Disorders and Stroke
7/1/03-6/30/08

3. Genetic Analysis of Familial Parkinson Disease Genes Pa
The recent identification of two genes that underlie familial inherited forms of PD, alpha-Synuclein (alpha-Syn) and Parkin, has afforded new clues regarding the molecular pathogenesis of PD. Interestingly, aggregates of alpha-Syn protein, along with ubiquitin, a protein degradation marker, appear to be major constituents of the intracytoplasmic inclusions that typify PD, termed Lewy bodies. Furthermore, the primary structure of Parkin displays sequence homology to ubiquitin ligases, implicating it directly in the ubiquitin/proteasome pathway. The analysis of alpha-Syn deficient animals suggests a role for alpha-Syn in the regulation of dopamine release at central synaptic terminals, but it remains unclear how this relates to the pathological activity of mutations in this gene.,I propose to test the hypothesis that these genes play roles in common genetic and biochemical pathways in familial PD. Questions that will be investigated include: --How do alpha-Syn and Parkin mutations cause dopamine neuron loss? --Do mutations in alpha-Syn and Parkin act within a common genetic pathway? --How do the normal activities of these proteins relate to their pathological functions?
National Institute of Neurological Disorders and Stroke
7/1/03-6/30/04

Parkinson's disease, gene expression, gene mutation, genetic disorder, neurogenetics, neuropathology, dopamine, neural degeneration, neuron, protein structure function, ubiquitin, gene targeting, immunocytochemistry, laboratory mouse, polymerase chain reaction, transgenic animal, western blotting