In the La Spada laboratory, we apply the tools of molecular genetics, neuroscience, and functional genomics to understand the mechanisms of neurodegenerative disease. While a M.D. – Ph.D. student at the University of Pennsylvania, Dr. La Spada discovered that X-linked spinal & bulbar muscular atrophy (SBMA) is caused by the expansion of a trinucleotide repeat sequence in the androgen receptor gene. As the very first disorder shown to result from an expanded repeat, this discovery of a novel type of genetic mutation led to the emergence of a new field of study. In 1998, our research program began with an emphasis on three inherited CAG–polyglutamine neurodegenerative disorders: SBMA, spinocerebellar ataxia type 7 (SCA7), and Huntington’s disease (HD). These disorders are all caused by CAG trinucleotide repeat expansions that encode expanded polyglutamine tracts in their respective disease proteins.
We have created mouse models for these diseases, and we have studied transcriptional dysregulation in these diseases, using a variety of genomics & proteomics approaches.
We have also generated cell culture and primary neuron models, and are adept at developing and characterizing human stem cell models using induced pluripotent stem cells (iPSCs).
Over the last decade, we have begun working on a number of related neurodegenerative disorders, and now have studies focused on amyotrophic lateral sclerosis (ALS), Alzheimer’s disease, and Parkinson’s disease. While these disorders may appear divergent, one key unifying theme has emerged: The molecular and cellular pathology underlying neurodegenerative disease is inextricably intertwined with homeostatic pathways that decline in function as we age, indicating that a thorough understanding of neurodegeneration cannot be achieved without defining the basic biology of age-dependent dysfunction. This realization has led us to focus on a set of interconnected processes that are fundamentally important for normal neural function and for disease pathogenesis, including transcription, metabolism, and proteostasis. We are thus interested in (macro)autophagy, a process of cellular self-digestion necessary for survival in the face of starvation, but adapted for removal of damaged organelles and proteins in higher organisms, and found to be critically important for CNS homeostasis. This work seeks to define regulatory processes by which metabolic information dictates protein / organelle quality control activity via input from key nutrient-sensing factors, such as MAP4K3 and mTORC1.
We continue to investigate how transcription is regulated in the nervous system and dysregulated in disease, with our most recent work emphasizing single cell analysis. Complementing these molecular investigations are studies of cell-cell communication, including efforts aimed at understanding skeletal muscle – motor neuron interaction in motor neuron disease and the functional signaling occurring between neurons, astrocytes, and microglia in the CNS.
Another significant emphasis has been on translational research and therapy development, with programs aimed at gene silencing of dominant disease protein expression (as successfully accomplished for SCA7), and focused upon the identification of small molecules intended to boost mitochondrial function, promote proteostasis, or inhibit mTORC1 activation, with lead compounds currently moving towards clinical testing in HD and SCA7.