or specific distinguishing features in these patients, and in fact, some had a relatively slow disease progression. In order to better understand the neurobiology of this association and to identify the earliest indications of Parkinson disease, we collaborated with Dr. Karen Berman’s neuroimaging group at the National Institute of Mental Health to conduct the only controlled PET imaging study performed to date. In 2012, we published the results of our initial study of PET findings in GBA1-associated Parkinson disease and in at-risk mutation carriers, and have subsequently greatly enriched our sample size, recruiting additional GBA1 homozygotes and heterozygotes. The subjects either had Parkinson disease, or had a first degree relative with Parkinsonism. Clinical evaluations, 18F-fluorodopa PET scanning and resting Cerebral Blood Flow (rCBF) studies were performed. Each group was compared to an age and sex matched control group, and, in total, more than 100 subjects were imaged. We noted that the pattern of dopamine loss in GBA1-associated PD is similar to sporadic PD, with the greatest loss seen in the caudal striatum. The rCBF studies demonstrated that subjects with GD and PD had less activity in specific brain regions affected in neurodegenerative disorders with cognitive impairment. Of the 21 subjects initially recruited with GBA1 mutations without parkinsonian manifestations, but with a positive family history of PD, only two showed early changes in fluorodopa. This confirms our clinical impression that most of our at- risk patients have not shown signs of developing Parkinson disease. Thus, with our current state of knowledge, it would be difficult to distinguish clinically who might best benefit from protective treatments. A better understanding of the other genetic or non-genetic risk factors that make our patients either more or less likely to develop Parkinson disease will be essential. Dr. Weinreb: What are we learning about GD cellular pathophysiology from your studies of GD monocyte-derived macrophages and cultured macrophages derived from induced pluripotent stem cells? Dr Sidransky: Studies into the pathogenesis of Gaucher disease have long suffered from the dearth of appropriate cellbased models exhibiting glycolipid storage. Thus, we generated Gaucher macrophage models by deriving primary macrophages from monocytes isolated from patients with different Gaucher genotypes, as well as from induced pluripotent stem cells (iPSCs) made from patient fibroblasts. We showed that both the primary and iPSC-derived Gaucher macrophages had reduced glucocerebrosidase activity, and that Gaucher, but not control macrophages exhibit significant glycolipid storage. We observed that Gaucher macrophages efficiently phagocytose E. coli, but had defects in chemotaxis. Moreover, reduced intracellular reactive oxygen species (ROS) production and impaired phagosome maturation in these Gaucher cells caused defective digestion of phagocytic material, providing new insights into the defect in this disorder. Our results were consistent in both primary and iPSC-derived macrophages with the same genotype. The macrophage models recapitulate the disease phenotype, opening a 16 Advances in Gaucher Disease much needed tool for drug and biomarker development and validation. Utilizing primary human macrophages derived from peripheral monocytes collected from 18 different patients with Gaucher disease, we further demonstrated a link between impaired autophagy and inflammasome activation in Gaucher macrophages, integrating the study of disease pathogenesis and macrophage biology with the pathways involved in autophagy and inflammation. Gaucher disease manifests with cytopenia, organomegaly and inflammation. Recently, it has been appreciated that autophagy is involved in the regulation of inflammation. Inflammasomes are multi-protein complexes located in the cytosol, which, trigger IL-1 activation and caspase 1 activation. We demonstrated that lysosomal dysfunction leads to impaired autophagy in Gaucher macrophages, which prevents the delivery of inflammasomes to autophagosomes and leads to increased secretion of the inflammatory cytokine IL-1. We showed that elevated p62 levels play a pivotal role in the polarization of Gaucher macrophages and that these macrophages manifest inflammatory phenotypes because of impaired autophagy. The inflammation identified may contribute to organomegaly, the tendency toward inflammation and specific malignancies in some patients, the debilitating bone disease and potentially the central nervous system involvement in neuronopathic Gaucher disease. The failure of fusion of autophagosomes with lysosomes may also be relevant to the association with Parkinson disease, for in neurodegenerative disorders impaired autophagic pathways fail to clear accumulated protein aggregates. This finding could provide new therapeutic targets. Dr. Weinreb: Your laboratory has identified some small molecule chaperone drugs that reverse many of the cellular abnormalities associated with GD. Could you summarize the most salient of these findings? Is there a likelihood that some of these drugs may be tested in human clinical trials in the near future? By enhancing wild type glucocerebrosidase activity, is there evidence that these drugs may also be effective for treating non-GD-associated Parkinson disease? Dr Sidransky: Yes, our group has been exploring chemical chaperones as a treatment approach for Gaucher disease with potential utility as a therapy for Parkinsonism. The justification for developing chaperones for glucocerebrosidase is that patients with Gaucher disease require life-long therapy, and available treatments are extremely expensive and inconvenient. A safe small molecule therapy should be easily administered, cheaper to produce and able to cross the blood-brain barrier and thus impact neuronopathic forms of the disorder. Chaperones could also function as enzyme-enhancing therapies to improve current therapeutics. Since there is currently no therapy that alters the neurodegenerative course of Parkinson disease, it is possible that stabilizing or enhancing glucocerebrosidase will obliterate the risk associated with mutations in this gene. Furthermore, if increasing glucocerebrosidase levels actually prevent -synuclein accu
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