Dementia is a debilitating neurological disorder resulting in the dysfunction of the cerebral cortex, the part of the brain controlling perception, memory, thoughts, language, and consciousness. Frontotemporal lobar degeneration (FTLD) is the most common cause of neurological impairment in the geriatric population, and represents a group of clinically, neuropathologically, and genetically heterogeneous disorders, with significant overlap between the neurodegenerative mechanism and the clinical phenotype. Amyotrophic lateral sclerosis (ALS) and FTLD are highly related conditions that are considered as part of a pathobiological spectrum, which begins in distinct regions of the body and propagates with age. Clinical pathology reveals the presence of aggregated protein inclusions that correspond to a loss of function in specific neuronal cell populations. To characterize how these pathobiological processes occur in the neuronal populations most susceptible to disease, I developed methods to direct the differentiation of human induced pluripotent stem (iPS) cells, derived from healthy and FTLD diseased human patient fibroblasts, into multiple cortical neuronal populations in vitro. Through a combination of hypothesis-driven and discovery-driven approaches, cortical neurons will be used to search for disease-relevant differences between healthy and ALS/FTLD patient- derived neurons. These cortical neurons will be compared in the presence or absence of environmental stressors to search for differences in survival, morphology, electrophysiology, and transcriptional profiles. Furthermore, the effect of mutations in the chromosome 9 open reading frame 72 (C9orf72), a gene implicated for its prominent role in both ALS and FTLD, will be studied from both transgenic mouse models and patient-derived human IPS cells. Taken together, these studies have the potential to identify novel environmental and genetic factors implicated in the progression of FTLD. Through the development of a human cell-based platform to model disease, coupled with known clinical and pathological symptoms, these studies would provide the foundation necessary to unravel the biological mechanisms of degeneration that occur in the aging brain.
Neurodegeneration is a very common manifestation of the aging process, which is becoming more prevalent due to increases in lifespan. Dementia associated with frontotemporal lobe degeneration (FTLD) and amyotrophic lateral sclerosis (ALS) are two related neurodegenerative diseases with similar molecular mechanisms that first present pathological symptoms in different classes of neurons with aging. This application will compare induced pluripotent stem cell-derived cortical projection neurons, made from healthy and FTLD human patients, to search for differences in gene expression, electrophysiological properties, and neurodegenerative pathology in order to explore the mechanisms that initiate, enhance, or propagate pathological phenotypes with age.