John Woulfe

Dr. Woulfe's research interests center on the role of alpha-synuclein aggregation in the pathophysiology of Parkinson's disease. In collaboration with Dr. Doug Gray, he is creating a novel mouse model which will allow the direct visualization of alpha-synuclein aggregation in Vivo. This tool will be used to explore environmental triggers that might initiate Parkinson's disease.

Neuronal Intranuclear Inclusions in Health and Disease

a) Tubulin-Immunoreactive Intarnuclear Inclusions in the Human Brain. Our group is exploring a novle type of intranuclear inclusion body in the normal human brain which we feel might reveal clues to intranuclear inclusion formation in neurodegenerative disease. These tubulin-immunoreactive neuronal intranuclear inclusions are present in the normal human brain (Woulfe and Munoz, 2000), and in certain brain tumours (ependymomas and gangliogliomas; Woulfe 2000). We have also demonstrated that these inclusions are significantly and substantially reduced in Alzheimer's disease. More recently, we have identified immunoreactivity for other proteins associated with these inclusions which could provide clues as to their function. We believe that these enigmatic intranuclear inclusions are the same rod-like inclusions described by the classical microscopists as early as 1894. These structures are thought to be related to neuronal activity, an observation that is interesting in the context of our findings in Alzheimer’s disease. The results of these ongoing studies may have important implications with respect to understanding the pathogenesis of Alzheimer's disease and other neurodegenerative diseases.

b) Ubiquitinated Neuronal Intranuclear Inclusions in Frontotemporal Dementia
We identified a subgroup of patients with this unique non-tau, non-synuclein related form of frontotemporal dementia. In these patients, abundant ubiquitinated neuronal intranuclear inclusions were found. Ubiquitinated intranuclear inclusions are a pathological feature of trinucleotide repeat disorders. The presence of intranuclear inclusions correlated with distinctive clinical features within the subjects, including a family history. The nosology of this group of diseases is in a state of flux characterized by ongoing debate among "lumpers" and "splitters". Our results would suggest that frontotemporal dementia of motor neuron disease type is a unique category, within which there is a neuropathologically-defined subset of patients. The presence of intranuclear inclusions in these patients may provide a clue to the pathogenesis of the disease.