Neuron cell biology of Parkinson's disease, tauopathies and primary mitochondrial diseases: autophagy, mitochondria & dendrite biology
Parkinson disease (PD) is an inexorably progressive neurodegenerative disease, whose symptoms include tremor, rigidity and diminishing speed and amplitude of movements. This leads to difficulty walking and impaired social interactions, exacerbated by depression or anxiety. Once thought to predominantly involve dopaminergic neurons in the midbrain, a significant pre-motor phase involving dysfunction of autonomic, olfactory, and cortical neurons is now recognized. Up to 35-40% of patients have cognitive-executive dysfunction at the time of initial diagnosis, with dementia eventually afflicting 80% of patients; mood disorders, apathy and delusions may also precede motor symptoms. Numerous lines of evidence indicate disruptions in mitochondrial homeostasis, autophagy-lysosomal recycling and cytoskeletal transport. Mutations in genes that affect these systems can cause either pediatric or adult neurodegeneration.
We utilize primary neurons, iPSC-derived neurons, patient brain tissues, and mouse models to study mechanisms underlying neurodegen-eration. Data from models based on familial PD or frontotemporal dementia genes or from toxins that mimic mitochondrial or oxidative stress observed in human neurodegenerative diseases are integrated to advance a conceptual framework positing that imbalanced, and thus maladaptive, stress responses permit or contribute to progression of the disease process. In recent years, our emphasis has shifted from neuron cell death to earlier, potentially reversible phases of mitochondrial dysregulation and synaptic loss. Through study of disease, we have discovered basic mechanisms regulating how neurons recycle mitochondria and are actively studying how mitochondria regulate expansion or retraction of synaptic networks.
Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, PA