PLD3 is a neuronal lysosomal phospholipase D associated with ß-amyloid plaques and cognitive function in Alzheimer's disease.

Phospholipase D3 (PLD3) is a protein of unclear function that structurally resembles other members of the phospholipase D superfamily. A coding variant in this gene confers increased risk for the development of Alzheimer's disease (AD), although the magnitude of this effect has been controversial. Because of the potential significance of this obscure protein, we undertook a study to observe its distribution in normal human brain and AD-affected brain, determine whether PLD3 is relevant to memory and cognition in sporadic AD, and to evaluate its molecular function. In human neuropathological samples, PLD3 was primarily found within neurons and colocalized with lysosome markers (LAMP2, progranulin, and cathepsins D and B). This colocalization was also present in AD brain with prominent enrichment on lysosomal accumulations within dystrophic neurites surrounding ß-amyloid plaques. This pattern of protein distribution was conserved in mouse brain in wild type and the 5xFAD mouse model of cerebral ß-amyloidosis. We discovered PLD3 has phospholipase D activity in lysosomes. A coding variant in PLD3 reported to confer AD risk significantly reduced enzymatic activity compared to wild-type PLD3. PLD3 mRNA levels in the human pre-frontal cortex inversely correlated with ß-amyloid pathology severity and rate of cognitive decline in 531 participants enrolled in the Religious Orders Study and Rush Memory and Aging Project. PLD3 levels across genetically diverse BXD mouse strains and strains crossed with 5xFAD mice correlated strongly with learning and memory performance in a fear conditioning task. In summary, this study identified a new functional mammalian phospholipase D isoform which is lysosomal and closely associated with both ß-amyloid pathology and cognition.

A draft conceptual model of SLC6A1 neurodevelopmental disorder.

Introduction: SLC6A1 Neurodevelopmental Disorder (SLC6A1-NDD), first described in 2015, is a rare syndrome caused by a mutation in the SLC6A1 gene which encodes for the GABA Transporter 1 (GAT-1) protein. Epilepsy is one of the most common symptoms in patients and is often the primary treatment target, though the severity of epilepsy is variable. The impact of seizures and other symptoms of SLC6A1-NDD on patients and caregivers is wide-ranging and has not been described in a formal disease concept study. Methods: A literature search was performed using the simple search term, "SLC6A1." Papers published before 2015, and those which did not describe the human neurodevelopmental disorder were removed from analysis. Open-ended interviews on lived experiences were conducted with two patient advocate key opinion leaders. An analysis of de-identified conversations between families of people with SLC6A1-NDD on social media was performed to quantify topics of concern. Results: Published literature described symptoms in all of the following domains: neurological, visual, motor, cognitive, communication, behavior, gastrointestinal, sleep, musculo-skeletal, and emotional in addition to epilepsy. Key opinion leaders noted two unpublished features: altered hand use in infants, and developmental regression with onset of epilepsy. Analysis of social media interactions confirmed that the core symptoms of epilepsy and autistic traits were prominent concerns, but also demonstrated that other symptoms have a large impact on family life. Discussion: For rare diseases, analysis of published literature is important, but may not be as comprehensive as that which can be gleaned from spontaneous interactions between families and through qualitative interviews. This report reflects our current understanding of the lived experience of SLC6A1-NDD. The discrepancy between the domains of disease reported in the literature and those discussed in patient conversations suggests that a formal qualitative interview-based disease concept study of SLC6A1-NDD is warranted.