Spectrins: molecular organizers and targets of neurological disorders.

Spectrins are cytoskeletal proteins that are expressed ubiquitously in the mammalian nervous system. Pathogenic variants in SPTAN1, SPTBN1, SPTBN2 and SPTBN4, four of the six genes encoding neuronal spectrins, cause neurological disorders. Despite their structural similarity and shared role as molecular organizers at the cell membrane, spectrins vary in expression, subcellular localization and specialization in neurons, and this variation partly underlies non-overlapping disease presentations across spectrinopathies. Here, we summarize recent progress in discerning the local and long-range organization and diverse functions of neuronal spectrins. We provide an overview of functional studies using mouse models, which, together with growing human genetic and clinical data, are helping to illuminate the aetiology of neurological spectrinopathies. These approaches are all critical on the path to plausible therapeutic solutions.

Instances of ocular findings in transgender patients undergoing hormonal therapy.

Purpose: To describe the ophthalmological manifestations in transgender patients on gender-affirming hormone therapy. Methods: A retrospective chart review study was conducted. Female-to-male (FTM) and male-to-female (MTF) transgenders on gender-affirming hormone therapy evaluated at a single center were included. Candidates were collected using a phrase-identifying search tool within the electronic medical record system. Descriptive analyses were conducted to report the demographics, hormonal therapies, clinical findings, and visual outcomes. Results: A total of 17 patients were included, seven were FTM, and ten were MTF transgenders. The median age was 26.0 years (range; 20.0-30.0) in the FTM group and 35.0 years (range; 23.0-67.0) in the MTF group. Testosterone therapy in FTM patients comprised 30-60 mg of intramuscular injections weekly or 50 mg of transdermal gel daily. MTF patients used mainly 2-4 mg of estradiol and 100-300 mg of spironolactone tablets daily. A total of 27 eyes were affected, 12 in FTM and 15 in MTF patients. The median visual acuity was 20/25 in FTM (range; 20/20-20/60) and 20/25 in MTF (range; 20/20-20/400). The most common diagnoses in FTM patients were neurologic (71.4 %), particularly idiopathic intracranial hypertension, while MTF transgenders presented mainly with chorioretinal diseases (40.0 %). Compliance with medical recommendations and follow-up appointments was seen in 71.4 % of FTM and 50.0 % of MTF patients. At the last visit, the median visual acuity was 20/50 (range; 20/20-20/70) in FTM and 20/25 (range; 20/20-20/70) in MTF patients. Conclusions and importance: Transgenders presented a variety of ocular findings. A cause-and-effect association cannot be stated, yet eye specialists must be cognizant of these findings to provide appropriate treatment.

TRIM67 regulates exocytic mode and neuronal morphogenesis via SNAP47.

Neuronal morphogenesis involves dramatic plasma membrane expansion, fueled by soluble N-ethylmaleimide-sensitive factor attachment protein eceptors (SNARE)-mediated exocytosis. Distinct fusion modes described at synapses include full-vesicle fusion (FVF) and kiss-and-run fusion (KNR). During FVF, lumenal cargo is secreted and vesicle membrane incorporates into the plasma membrane. During KNR, a transient fusion pore secretes cargo but closes without membrane addition. In contrast, fusion modes are not described in developing neurons. Here, we resolve individual exocytic events in developing murine cortical neurons and use classification tools to identify four distinguishable fusion modes: two FVF-like modes that insert membrane material and two KNR-like modes that do not. Discrete fluorescence profiles suggest distinct behavior of the fusion pore. Simulations and experiments agree that FVF-like exocytosis provides sufficient membrane material for morphogenesis. We find the E3 ubiquitin ligase TRIM67 promotes FVF-like exocytosis in part by limiting incorporation of the Qb/Qc SNARE SNAP47 into SNARE complexes and, thus, SNAP47 involvement in exocytosis.

Pathogenic SPTBN1 variants cause an autosomal dominant neurodevelopmental syndrome.

SPTBN1 encodes ßII-spectrin, the ubiquitously expressed ß-spectrin that forms micrometer-scale networks associated with plasma membranes. Mice deficient in neuronal ßII-spectrin have defects in cortical organization, developmental delay and behavioral deficiencies. These phenotypes, while less severe, are observed in haploinsufficient animals, suggesting that individuals carrying heterozygous SPTBN1 variants may also show measurable compromise of neural development and function. Here we identify heterozygous SPTBN1 variants in 29 individuals with developmental, language and motor delays; mild to severe intellectual disability; autistic features; seizures; behavioral and movement abnormalities; hypotonia; and variable dysmorphic facial features. We show that these SPTBN1 variants lead to effects that affect ßII-spectrin stability, disrupt binding to key molecular partners, and disturb cytoskeleton organization and dynamics. Our studies define SPTBN1 variants as the genetic basis of a neurodevelopmental syndrome, expand the set of spectrinopathies affecting the brain and underscore the critical role of ßII-spectrin in the central nervous system.

Recent progress and considerations for AAV gene therapies targeting the central nervous system.

BACKGROUND: Neurodevelopmental disorders, as a class of diseases, have been particularly difficult to treat even when the underlying cause(s), such as genetic alterations, are understood. What treatments do exist are generally not curative and instead seek to improve quality of life for affected individuals. The advent of gene therapy via gene replacement offers the potential for transformative therapies to slow or even stop disease progression for current patients and perhaps minimize or prevent the appearance of symptoms in future patients. MAIN BODY: This review focuses on adeno-associated virus (AAV) gene therapies for diseases of the central nervous system. An overview of advances in AAV vector design for therapy is provided, along with a description of current strategies to develop AAV vectors with tailored tropism. Next, progress towards treatment of neurodegenerative diseases is presented at both the pre-clinical and clinical stages, focusing on a few select diseases to highlight broad categories of therapeutic parameters. Special considerations for more challenging cases are then discussed in addition to the immunological aspects of gene therapy. CONCLUSION: With the promising clinical trial results that have been observed for the latest AAV gene therapies and continued pre-clinical successes, the question is no longer whether a therapy can be developed for certain neurodevelopmental disorders, but rather, how quickly.