Rett syndrome (RTT) is a severe neurodevelopmental disorder primarily attributed to mutations in the methyl CpG-binding protein 2 (MeCP2) gene. Functioning as a key player in various cellular processes like transcriptional regulation, chromatin remodeling, and RNA splicing, the MeCP2 protein's significance is paramount. Leveraging human cellular models such as ESCs, iPSCs, and NPCs has proven instrumental in comprehending intricate disorders like RTT. These models faithfully replicate disease-related neural developmental changes, effectively bridging the gap between animal studies and human pathophysiology. Our research lab is dedicated to investigating the pathological molecular mechanisms of RTT, with a specific focus on the disruption of non-coding RNAs (ncRNAs). After establishing a human cellular model to mimic the early stages of neural development in vitro, we performed a single cell RNA sequencing to understand the population dynamics in the course of 30 days after induced neural differentiation. Cells deficient in MeCP2 demonstrated compromised proliferation alongside an imbalanced ratio of neurons to glial cells. Differential gene expression analysis revealed a significant downregulation of NEAT1, a long noncoding RNA pivotal in subnuclear domain formation known as paraspeckles, as well as in the regulation of genes involved in mitochondrial function and stress response. Elevated NEAT1 levels in patient samples further corroborated the ncRNA's dysregulation in RTT. In the absence of NEAT1, neural progenitor cells exhibited decreased proliferation rates, reduced neurosphere sizes, and aberrant protein aggregation. Both the MECP2 knockout and NEAT1 models exhibited deviations in autophagy-related vesicle counts, elevated lysosomal protein levels, and compromised mitochondrial integrity. These structural deficiencies contributed to impaired neuron arborizations and complexity, resulting in decreased spine and branch density. However, reintroduction of NEAT1 in MECP2 knockout model partially restored neuronal complexity, ameliorating RTT phenotype. NEAT1 emerges as a pivotal long ncRNA with great significance for RTT, playing a critical role in stress-related brain processes. The absence of NEAT1 contributes to RTT pathology, while its manipulation ameliorates the immature phenotype of RTT neurons, emphasizing its potential as a therapeutic target for Rett syndrome.

Introduction: Due to severe multiple disabilities in individuals with Rett syndrome, a lifelong need for care and advocacy is required to be done by the parents. Individuals with Rett syndrome can live long into adulthood and for most of the parents that implies a lifelong parenting role, which calls for the development of a sustainable parenting role. To support the parents in the development and maintenance of their parenting role, we need to determine what positively and negatively affects them in different phases of the trajectory of their parenting role, and if there are certain situations that seems to be particularly vulnerable. First person descriptions can be an effective way to obtain this knowledge but has only been scarcely done. The aim of this study was to explore the experiences of being a parent of an individual with Rett syndrome in a lifelong perspective.

Methods:  From March-June 2023, 13 interviews were conducted using a semi-structured interview guide. Twelve mothers and eight fathers of 12 individuals with Rett syndrome were interviewed. Seven interviews were conducted with couples living together, and six interviews were conducted with one parent alone. A hermeneutic phenomenological approach was used to analyze the data.

Results: Preliminary analysis showed two main themes and seven subthemes which described a wide range of responsibilities and challenges. The first main theme was “Caretaking throughout the years”, with the subthemes “Chronical homework”, “Come what may”, “It’s been tough but also enriching”, “The endless responsibility”. The second main theme was “Distance and Nearness”, with the sub-themes “Creating the right distance”, “Living together, separately or together apart”, “I hope I outlive her”.

Discussion/Conclusion: A lifelong parenting role was described, with a high amount of responsibility and work related to caretaking that merged with the unconditional parental love. A lot of the caretaking the parents must commit to resembles the work that professional caregivers do, especially when the individual with Rett syndrome is living at home. When the individual with Rett syndrome has moved away from home, the parents still have different tasks they commit to e.g., apply for aids, advocate for the individual with Rett syndrome, or taking the individual with Rett syndrome to appointments at the hospital. Furthermore, the parents act as experts in different situations being the ones knowing the individual with Rett syndrome the best.