Jacqueline G Lu

All Publications

• Synaptogenic effect of APP-Swedish mutation in familial Alzheimer's disease. Science translational medicine Zhou, B., Lu, J. G., Siddu, A., Wernig, M., Sudhof, T. C. 2022; 14 (667): eabn9380

  Abstract

  Mutations in beta-amyloid (Abeta) precursor protein (APP) cause familial Alzheimer's disease (AD) probably by enhancing Abeta peptides production from APP. An antibody targeting Abeta (aducanumab) was approved as an AD treatment; however, some Abeta antibodies have been reported to accelerate, instead of ameliorating, cognitive decline in individuals with AD. Using conditional APP mutations in human neurons for perfect isogenic controls and translational relevance, we found that the APP-Swedish mutation in familial AD increased synapse numbers and synaptic transmission, whereas the APP deletion decreased synapse numbers and synaptic transmission. Inhibition of BACE1, the protease that initiates Abeta production from APP, lowered synapse numbers, suppressed synaptic transmission in wild-type neurons, and occluded the phenotype of APP-Swedish-mutant neurons. Modest elevations of Abeta, conversely, elevated synapse numbers and synaptic transmission. Thus, the familial AD-linked APP-Swedish mutation under physiologically relevant conditions increased synaptic connectivity in human neurons via a modestly enhanced production of Abeta. These data are consistent with the relative inefficacy of BACE1 and anti-Abeta treatments in AD and the chronic nature of AD pathogenesis, suggesting that AD pathogenesis is not simply caused by overproduction of toxic Abeta but rather by a long-term effect of elevated Abeta concentrations.

  View details for DOI 10.1126/scitranslmed.abn9380

  View details for PubMedID 36260691

• A novel PRRT2 pathogenic variant in a family with paroxysmal kinesigenic dyskinesia and benign familial infantile seizures COLD SPRING HARBOR MOLECULAR CASE STUDIES Lu, J. G., Bishop, J., Cheyette, S., Zhulin, I. B., Guo, S., Sobreira, N., Brenner, S. E. 2018; 4 (1)

  Abstract

  Paroxysmal kinesigenic dyskinesia (PKD) is a rare neurological disorder characterized by recurrent attacks of dyskinetic movements without alteration of consciousness that are often triggered by the initiation of voluntary movements. Whole-exome sequencing has revealed a cluster of pathogenic variants in PRRT2 (proline-rich transmembrane protein), a gene with a function in synaptic regulation that remains poorly understood. Here, we report the discovery of a novel PRRT2 pathogenic variant inherited in an autosomal dominant pattern in a family with PKD and benign familial infantile seizures (BFIS). After targeted Sanger sequencing did not identify the presence of previously described PRRT2 pathogenic variants, we carried out whole-exome sequencing in the proband and her affected paternal grandfather. This led to the discovery of a novel PRRT2 variant, NM_001256442:exon3:c.C959T/NP_660282.2:p.A320V, altering an evolutionarily conserved alanine at the amino acid position 320 located in the M2 transmembrane region. Sanger sequencing further confirmed the presence of this variant in four affected family members (paternal grandfather, father, brother, and proband) and its absence in two unaffected ones (paternal grandmother and mother). This newly found variant further reinforces the importance of PRRT2 in PKD, BFIS, and possibly other movement disorders. Future functional studies using animal models and human pluripotent stem cell models will provide new insights into the role of PRRT2 and the significance of this variant in regulating neural development and/or function.

  View details for DOI 10.1101/mcs.a002287

  View details for Web of Science ID 000449982700004

  View details for PubMedID 29167286

  View details for PubMedCentralID PMC5793775