ID: 163: Contribution of the JAK/STAT pathway to neurodegenerative diseases

Abstract

Multiple Sclerosis (MS) is a chronic inflammatory and neurodegenerative disease of the CNS, characterized by inflammation, demyelination and axonal damage. Cells of the innate (macrophages, microglia, neutrophils) and adaptive (T-cells, B-cells) immune system contribute to both the pathology and repair of MS. Parkinson’s Disease (PD) is a neurodegenerative disease characterized by the deterioration of motor activities that are controlled by the nigrostriatal system. The motor symptoms of PD result from the progressive and selective loss of dopaminergic (DA) neurons in the midbrain substantia nigra pars compacta. Additionally, the PD brain is characterized by cytoplasmic and neuritic fibrillar α -synuclein ( α -syn) inclusions (known as Lewy bodies (LB) and Lewy neurites (LN), respectively). Recently, an impressive number of publications have implicated inflammation as a major pathogenic factor in PD, with involvement of both innate and adaptive immune cells. MS and PD are characterized by abundant production of cytokines that activate and regulate the functions of immune and glial cells. The Janus Kinase (JAK)/Signal Transducer and Activator of Transcription (STAT) pathway is the major signaling system utilized by cytokines, and is critical for development, regulation and termination of innate and adaptive responses. Dysregulation of the JAK/STAT pathway has pathological implications for a number of autoimmune and neuroinflammatory diseases. We have documented aberrant activation of the JAK/STAT pathway in pre-clinical models of both MS and PD. We will discuss the efficacy of inhibitors of the JAK pathway, known as Jakinibs, in these pre-clinical models, and describe the mechanisms that underlie their beneficial effects on neuroinflammation and neurodegenerative responses.