Dr. Albert R. La Spada

In my laboratory, we apply the tools of molecular genetics, neuroscience, and functional genomics to understand the mechanisms of neurodegenerative diseases and thereby develop meaningful therapies for them. Within the last decade, it has become clear that a key question in the neurodegenerative disease field is the selective vulnerability of different neuronal populations in different diseases. Inherited disorders such as Huntington's disease, various spinocerebellar ataxias, and X-linked spinobulbar muscular atrophy are characterized by widespread expression of a mutant gene product throughout the central nervous system but display well circumscribed patterns of neuronal dysfunction and demise. This theme is also apparent in genetic examples of common neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis (ALS), and prion disease. In the case of ALS1, the situation is remarkably dramatic as the mutant gene product (superoxide dismutase-1) is expressed in every cell of the body - yet only motor neurons degenerate! The overriding focus of my research program is to understand why different populations of neurons degenerate in different diseases, as I believe that this problem is fundamental to our understanding of the mechanistic basis of all neurodegenerative disorders.

I have chosen to devote a major portion of our effort in the lab to determining the molecular basis of the so-called CAG / polyglutamine repeat diseases of which there are nine: Huntington's disease (HD), X-linked spinal and bulbar muscular atrophy (SBMA), dentatorubral-pallidoluysian atrophy (DRPLA), and six forms of spinocerebellar ataxia (SCA1, 2, 3, 6, 7 & 17). In 1991, I discovered this novel type of genetic mutation while working on SBMA. Interestingly, it appears that these nine CAG trinucleotide repeat diseases are caused by the expansion of a tract of glutamine residues within proteins that are unrelated to one another. As the patterns of expression of the different disease genes are widespread and overlapping throughout the neuraxis, the CAG / polyglutamine diseases represent an excellent example of neuronal selectivity. Thus, insights into the basis of selective neurodegeneration in these disorders may be relevant to understanding this phenomenon in a wide range of neurological disease processes. When I first started my lab, I chose to focus my research efforts on two of these polyglutamine repeat diseases - SCA7 and SBMA.

A productive strategy for determining the molecular basis of a disease process and for providing an avenue for therapeutic advance has been the development of animal models of human diseases. I have applied this strategy in my studies of SCA7 and SBMA, and have used the mouse as the model system for study of these diseases. The mouse was selected because its neuroanatomy and physiology are similar to that of humans and its complement of genes, gene products, and molecular pathways share remarkable conservation with humans. Furthermore, its generation time and lifespan are tractable, and most importantly, genetic engineering technologies have been developed that permit highly accurate and rapid introduction of specific genetic alterations into its genome. Using this approach, we successfully modeled the retinal and brainstem degeneration in human SCA7 patients in the mouse, and used this model to obtain a mechanistic explanation for the rather selective cone-rod dystrophy retinal degeneration seen in human patients. Our model indicates that the polyglutamine-expanded version of ataxin-7 causes disease pathogenesis by interfering with the function of a transcription factor whose expression pattern is principally restricted to the photoreceptor nuclei and other retinal neuronal nuclei. This finding supported the concept that polyglutamine diseases involve transcription dysregulation as a key feature and suggests obvious modes of therapeutic intervention. Most recently, we have learned that ataxin-7 is a transcription factor, and have found evidence for a dominant negative effect of the polyglutamine expansion upon the transcription co-activator complex of which ataxin-7 is a part.

We have at the same time been able to produce a highly representative YAC model of SBMA, recapitulating all the key features of this disorder including its motor neuronopathy phenotype, gender-dependent degeneration, and late age of disease onset. With this highly useful model of SBMA, we determined that interruption of the expression of a certain growth factor was likely a key event in SBMA disease pathogenesis. The importance of this factor, vascular endothelial growth factor (VEGF), is becoming apparent for other related motor neuron diseases, such as especially ALS. Our work on SBMA suggests that various motor neuron diseases might involve disruption of the VEGF expression axis, and thus that VEGF expression is a critical response for sustaining the health and survival of motor neurons in the face of some type of stress.

In addition to finding strong evidence for the role of transcription dysregulation in polyglutamine disease pathogenesis, we are also learning that apoptotic activation and proteolytic cleavage are integral parts of the neuron disease process in the polyglutamine repeat diseases. Our latest data suggest that truncated polyglutamine protein products (produced in neurons of patients and of mice suffering with these diseases) can activate the intrinsic pathway of apoptosis in primary neurons in culture. Recent studies of polyglutamine-expanded AR are now linking the initiation of the apoptotic activation pathway with the autophagy pathway.

Our most recent project stems from our discovery of the gene responsible for the Purkinje cell degeneration (pcd) mouse mutant. This finding has led to an interesting conundrum: How does loss of a protease result in the selective degeneration of certain neuronal populations? This work represents a nice complement to our studies of proteolytic cleavage in the polyglutamine diseases and to our findings of non-cell autonomous Purkinje cell degeneration in SCA7 which is another active area of research for my group.

As this summary of our work should indicate, I am engaged in research aimed at understanding how neurons degenerate and why the degeneration is restricted to certain cell types in different diseases. As success in this endeavor requires interdisciplinary approaches and active collaboration, my philosophy has been to interact with a wide range of colleagues to move our work forward as quickly and in as many exciting directions as possible. While our future studies will principally rely upon a functional genomics approach coupled to the use of cutting edge neuroscience strategies, I am excited about the prospect of integrating emerging physical chemistry, protein biochemistry (proteomics) and structural biology approaches. Our long-term goal is to take the information that we acquire from all such studies, and use it to develop meaningful therapies for currently untreatable neurodegenerative disorders.