UC Riverside

Multiple Sclerosis (MS) is an autoimmune demyelinating disease of the central nervous system that leads to significant motor, cognitive and visual disability. Approximately 80% of MS patients have inflammatory demyelination within the cerebellum and present with tremors, impaired motor control and loss of coordination. While most MS patients exhibit symptoms indicative of cerebellar dysfunction, the pathophysiology of cerebellar symptoms in MS is complex and remains to be elucidated. Purkinje cells (PCs) are a class of myelinated gamma- aminobutyric acid (GABA)ergic neurons located solely in the cerebellum. These specialized neurons are the sole output of the cerebellar cortex and thus are an essential component of cerebellar circuitry. I hypothesize that, while immune cell infiltration and demyelination have been shown to contribute to PC dysfunction, another source of PC dysfunction may arise directly from metabolic deficits due to mitochondrial pathology. PCs require higher metabolic activity due to their extensively branched dendritic arbors in addition to the large number of glutamatergic inputs they receive from climbing and parallel fiber innervation. Mitochondrial dysfunction in neurons has been shown to contribute to MS disease mechanisms, as shown in human post-mortem MS brain tissue. Understanding the pathology and repair of dysfunctional Purkinje cells (PCs) will aid in the search for reparative and regenerative therapeutic approaches in MS patients. In this dissertation, I will test my hypothesis by investigating the role of cerebellar dysfunction during disease progression in both the experimental autoimmune encephalomyelitis (EAE) and cuprizone mouse models of MS while also assessing the treatment effects of Chloroindazole, an estrogen receptor beta (ER beta) ligand that has previously been shown to stimulate myelination and neuroprotection. Understanding the pathophysiology of mitochondria dysfunction in mouse models of MS while also elucidating the mechanism of action of remyelinating drugs on mitochondria for neuroprotection will help us identify superior therapeutics and improve the quality of life for patients with MS.