Phyllis L Faust, MD, PhD

Dr. Faust is a cellular neurobiologist who has pioneered studies on the biology of essential tremor (ET), one of the most common tremor disorders of humans. Her investigations on ET pathology in human autopsy brains, acquired through the Essential Tremor Centralized Repository at the NY Brain Bank (a joint effort between Dr. Elan Louis at UT Southwestern and Columbia University investigators), have been seminal in defining that the cerebellum is a major brain region that may drive tremor generation in ET. Major goals of our studies are to define morphological and molecular maps of biological changes in the human ET brain across the tremor circuit.

Our laboratory has identified degenerative changes centered on the cerebellar Purkinje cell and adjacent neuronal populations (basket cells, climbing fibers) as core biologic features in ET. We use techniques ranging from quantitative morphologic methods in brain tissue sections to identify disease associated changes, Western blot analyses, RNA-sequencing transcriptomics and laser capture microdissection to target specific cell populations in the brain for subsequent transcriptomic and proteomic analyses. These studies have begun to identify novel disease mechanisms in the ET cerebellum.

We are also investigating how these morphologic and molecular patterns in ET fit within the spectrum of changes seen in primary cerebellar degenerative disorders (e.g., spinocerebellar ataxias (SCAs), multiple system atrophy (MSA)) and diseases where the cerebellum is also postulated to play a role in tremor generation (e.g., Parkinson’s disease, dystonic tremor). We designed a novel approach that enables statistical comparisons based on composite analyses of multiple quantitative morphological metrics (“Patholog-omics”). Comparative analyses across morphologic categories demonstrates differences in relative expression of cerebellar changes, defining distinctive patterns in these groups. Our clinical and pathological studies support an emerging postulate that the degree of cerebellar degeneration in ET aligns it with a milder end in the spectrum of cerebellar degenerative disorders.

We are continuing to map out the out pathological changes in ET versus control autopsy brain specimens across cerebellar functional/anatomic compartments. We will determine the extent to which the pathological changes we have observed in one neocerebellar region may be distributed throughout the ET cerebellum versus their preferential involvement of certain cerebellar subregions, depending on specific clinical features in patients. We are also examining whether the degenerative changes in ET are restricted to the cerebellum or more broadly involve other structures in the cerebello-thalamo-cortical loop and olivo-cerebellar loop, which are physiological networks posited to be involved in the origins and propagation of tremor in ET. Morphological studies will be combined with proteomic analyses in cerebellar cortex, Purkinje cells, dentate nucleus and inferior olive, representing three key regions of the tremor circuit in ET versus control brains.

We have also recently identified that defects in cerebellar endoplasmic reticulum calcium handling are linked to ET, and in collaboration with Dr. Sheng-Han Kuo in Neurology are investigating the physiological and pathological effects of this alteration in a novel mouse model.