Biology subjects

Rudolph, I.-M.

Publications and source records attributed to Rudolph, I.-M..

4 recordsLinked to original sources

bioRxiv2026

A scalable human neuromuscular organoid platform enables lineage-specific analysis of drug responses in spinal muscular atrophy.

Scalable human models that capture interactions between distinct tissues remain limited, constraining mechanistic insight and therapeutic prediction. Here, we established a scalable, automation-compatible human neuromuscular organoid (NMO) platform that enables integrated analysis of neuronal and muscle lineages in spinal muscular atrophy (SMA). Patient-derived NMOs reproducibly self-organise into spinal cord and skeletal muscle compartments and form functional neuromuscular circuits. SMA NMOs recapitulate early disease features, including reduced survival motor neuron (SMN) protein levels and impaired neuromuscular junction (NMJ) maturation. Single-nucleus RNA sequencing identifies lineage-specific transcriptional changes across neuronal and muscle compartments preceding functional deficits. Using this platform, we compared two clinically relevant SMN2 splicing modulators and observed distinct, cell-type-dependent responses. While both compounds increased SMN levels and NMJ number, only one enhanced myofiber growth and improved contractile function. These findings highlight muscle maturation, rather than NMJ number alone, as a key determinant of functional recovery and establish NMOs as a scalable system for studying cell-type-specific therapeutic responses.

bioengineering↗

bioRxiv2025

Alzheimer disease risk variant rs11218343 determines functional expression of SORL1 in microglia

IntroductionRs11218343 is a non-coding variant of genome-wide significance for sporadic Alzheimers disease (AD) with one of the most protective effects known. It localizes to SORL1, encoding the AD risk factor SORLA. Still, the functional significance of rs11218343 for AD related processes remains unclear. MethodsWe used iPSC lines from donors, or genome-engineered to carry major and minor rs11218343 alleles, to study the impact of rs11218343 genotype on brain cell activities. ResultsWe show that rs11218343 uniquely controls functional expression of SORLA in microglia, with incrased receptor expression in the minor protective allele correlating with reduced pro-inflammatory responses. This anti-inflammatory effect is seen in donor iPSC lines but not in SNP-engineered isogenic lines, documenting rs11218343 to be diagnostic but not functional. DiscussionOur findings corroborate genetically defined expression levels of SORL1 in microglia as a determinant of protection from pro-inflammatory stimulation, a function encoded by a haplotype linked to rs11218343. RESEARCH IN CONTEXTO_ST_ABSSystematic reviewC_ST_ABSReviewing the literature on single nucleotide polymorphisms (SNP) showing genome-wide association with the risk of sporadic AD, we learned that prior studies identified rs11218343 as a major predictor of protection from the disease. We also learned that this SNP localizes to SORL1, encoding the AD risk factor SORLA. However, no data were available whether this SNP controls functional expression of SORLA or other AD-related proteins in brain cell types. InterpretationOur study documents that rs11218343 controls the expression of SORL1 in iPSC-derived human microglia, an effect not seen for other microglial genes. Increased expression of SORLA in the minor allele correlates with decreased inflammatory responses in this cell type. These findings suggest that the ability of SORLA to contain pro-inflammatory actions of microglia contributes to its protective effect in AD. Future directionsOur studies document rs11218343 to be diagnostic but not functional in SORL1 expression control. These findings should be corroborated in a replication cohort of donor cell lines. Also, further analyses need to identify the sequence variation in disequilibrium with rs11218343, that controls SORL1 gene transcription. Such information will be essential to mechanistically resolve the mode of action of the most protective genotype in sporadic AD known to date. HIGHLIGHTSO_LIrs11218343 predicts expressions of AD risk gene SORL1 C_LIO_LIexpression control by the linked haplotype is specific to human microglia C_LIO_LIincreased SORL1 levels with minor allele ameliorates pro-inflammatory responses C_LI

genetics↗

bioRxiv2025

Familial Alzheimer disease mutation identifies novel role of SORLA in release of neurotrophic exosomes

Sortilin-related receptor with A-type repeats (SORLA) is an intracellular sorting receptor that directs target proteins between endocytic and secretory compartments of cells. Mutations in SORL1, encoding SORLA, are common in individuals suffering from Alzheimer disease (AD) of unknown etiology. Conceptually, characterization of inheritable SORL1 variants associated with AD can provide important new information about functions of this receptor relevant for aging brain health. Here, we focused on elucidation of the AD-associated variant SORLA N1358S, carrying a mutation in the main ligand binding domain of the receptor. Using unbiased quantitative proteome screens, we identified major alterations in the mutant receptor interactome linked to biogenesis and secretion of exosomes. Using advanced biophysical, cell biological, as well as functional studies in stem cell-derived human cell models we corroborated impaired release and loss of neurotrophic action of exosomes from neurons and microglia expressing SORLAN1358S. An impaired neurotrophic potential was attributed to an altered exosomal content of RNA binding proteins and associated microRNAs, known to control neuronal growth and maturation. Our studies identified a so far unknown function for SORLA in controlling the quantity and trophic quality of extracellular vesicles secreted by cells, and they argue for impaired cellular cross talk through exosomes as a pathological trail contributing to the risk of AD seen with carriers of SORL1 variants.

neuroscience↗

bioRxiv2024

Interaction of sortilin with apolipoprotein E3 enables neurons to use long-chain fatty acids as alternative metabolic fuel

Sortilin (SORT1) is a lipoprotein receptor that shows genome-wide association with hypercholesterolemia, explained by its ability to control hepatic output of lipoproteins. Remarkably, SORT1 also shows genome-wide association with Alzheimer disease (AD) and frontotemporal lobe dementia, the most prevalent forms of age-related dementias. Yet, sortilins contribution to human brain lipid metabolism and health remains unclear. Using humanized mouse strains and iPSC-based cell models of brain lipid homeostasis, we document that sortilin mediates neuronal uptake of polyunsaturated fatty acids carried by apoE. Internalized lipids are converted into ligands for PPAR, inducing transcription profiles that enable neurons to use long-chain fatty acids as metabolic fuel. This pathway works with apoE3, but is lost with the AD risk factor apoE4, which disrupts sortilins endocytic activity. We document a role for the lipoprotein receptor sortilin in metabolic fuel choice in neurons, possibly crucial when supply with glucose is limited, as in the aging brain.

neuroscience↗