Autoantibodies to brain proteins are present in Juvenile Neuronal Ceroid Lipofuscinosis (Batten disease) patients and the Cln3−/− mouse model of this disease, suggesting an autoimmune component to pathogenesis. Using genetic or pharmaceutical approaches to attenuate this immune response in Cln3−/− mice, we demonstrate decreased neuroinflammation, decreased deposition of Immunoglobulin G in the brain and protection of vulnerable neuron populations. Moreover, immune suppression results in a significant improvement in motor performance providing for the first plausible therapeutic approach for juvenile Batten disease.
Neuronal Ceroid Lipofuscinoses (NCLs) have an incidence of 1 in 12,500 live births. These devastating neurodegenerative lysosomal storage diseases are characterized by the lysosomal accumulation of autofluorescent storage material (AFSM) similar to that seen in aging cells. Using patient derived lymphoblasts from three genetically distinct NCLs we report that AFSM for each NCL has distinct spectral properties. Moreover, by using pharmacological inhibitors to disrupt various biochemical pathways in normal control lymphoblasts we have determined that disruptions in microtubule assembly and non-muscle myosin II function results in accumulation of lysosomal AFSM. Interestingly, inhibition of autophagy did not result in AFSM. We conclude that cellular disturbances outside the lysosome in addition to compromised function of this organelle can result in accumulation of lysosomal AFSM in NCLs and possibly as a result of cellular aging.
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