The TMEM106B T186S coding variant increases neurite arborization and synaptic density in primary hippocampal neurons
Year: 2023
Type: article
Abstract: The lysosomal protein TMEM106B was identified as a risk modifier of multiple dementias including frontotemporal dementia and Alzheimer’s disease. The gene comes in two major haplotypes, one associated with disease risk, and by comparison, the other with resilience. Only one coding polymorphism distinguishes the two alleles, a threonine-to-serine substitution at residue 185 (186 in mouse), that is inherited in disequilibrium with multiple non-coding variants. Transcriptional studies suggest synaptic, neuronal, and cognitive preservation in human subjects with the protective haplotype, while murine in vitro studies reveal dramatic effects of TMEM106B deletion on neuronal development. Despite this foundation, the field has not yet resolved whether coding variant is biologically meaningful, and if so, whether it has any specific effect on neuronal phenotypes. Here we studied how loss of TMEM106B or expression of the lone coding variant in isolation affected transcriptional signatures in the mature brain and neuronal structure during development in primary neurons. Homozygous expression of the TMEM106B T186S variant in knock-in mice increased cortical expression of genes associated with excitatory synaptic function and axon outgrowth, and promoted neurite branching, dendritic spine density, and synaptic density in primary hippocampal neurons. In contrast, constitutive TMEM106B deletion affected transcriptional signatures of myelination without altering neuronal development in vitro. Our findings show that the T186S variant is functionally relevant and may contribute to disease resilience during neurodevelopment.
Source: Frontiers in Neuroscience
Authors: Quynh Nguyen, Caleb A. Wood, Peter J. Kim, Joanna L. Jankowsky
Institution: Baylor College of Medicine
Language: English
Subfield: Physiology
Field: Medicine
Domain: Health Sciences
Open Access status: gold
Estimated APC paid: $3,295
Awards: Circuit-based mechanisms of neuronal vulnerability in the adult EC, Modeling genetic modifiers of cognitive reserve in AD, TMEM106b as a lysosomal safeguard of cognitive function, Plasticity of the entorhinal-hippocampal circuit as a vulnerability in AD, Lysosome Regulation and Signaling in Aging and Alzheimer's Disease
OpenAlex ID: W4387607659