STXBP1encephalopathy

Abstract

De novo pathogenic variants in STXBP1 encoding syntaxin1-binding protein (STXBP1, also known as Munc18-1) lead to a range of early-onset neurocognitive conditions, most commonly early infantile epileptic encephalopathy type 4 (EIEE4, also called STXBP1 encephalopathy), a severe form of epilepsy associated with developmental delay/intellectual disability. Other neurologic features include autism spectrum disorder and movement disorders. The progression of neurologic symptoms has been reported in a few older affected individuals, with the appearance of extrapyramidal features, reminiscent of early onset parkinsonism. Understanding the pathologic process is critical to improving therapies, as currently available antiepileptic drugs have shown limited success in controlling seizures in EIEE4 and there is no precision medication approach for the other neurologic features of the disorder. Basic research shows that genetic knockout of STXBP1 or other presynaptic proteins of the exocytic machinery leads to widespread perinatal neurodegeneration. The mechanism that regulates this effect is under scrutiny but shares intriguing hallmarks with classical neurodegenerative diseases, albeit appearing early during brain development. Most critically, recent evidence has revealed that STXBP1 controls the self-replicating aggregation of α-synuclein, a presynaptic protein involved in various neurodegenerative diseases that are collectively known as synucleinopathies, including Parkinson disease. In this review, we examine the tantalizing link among STXBP1 function, EIEE, and the neurodegenerative synucleinopathies, and suggest that neural development in EIEE could be further affected by concurrent synucleinopathic mechanisms.

Cortical proteins may provide motor resilience in older adults

“…4 B). Inspection of the peptides clustering within each factor suggests that each factor may represent a distinct biological function (Supplementary Table 3 ) for example cell structure integrity 12 – 14 , synaptic plasticity 15 – 20 , mitochondrial bioenergetics, signal transduction and cell proliferation 4 , 21 – 27 and amyloid 28 .…”

STXBP1 encephalopathies: Clinical spectrum, disease mechanisms, and therapeutic strategies

“…A misfolded protein that is prone to degradation and aggregation may also destabilize and co‐aggregate the proteins it is directly bound to. Interestingly, co‐aggregation of mutant STXBP1 with alpha‐synuclein has been proposed (Chai et al 2016), which may explain the Parkinsonian symptoms seen in some older patients (Lanoue et al 2019). It remains to be seen whether this effect is also present in other types of mutations in which part of the protein, presumably containing the motif that is responsible for binding of STXBP1 to its interactors, remains intact.…”

Presynaptic dysfunction in neurodevelopmental disorders: Insights from the synaptic vesicle life cycle

“…In fact, de novo mutations in STXBP1 are among the most frequent causes of epilepsies and encephalopathies with most patients also having severe to profound intellectual disability and movement disorders (Stamberger et al., 2016). More than 85 pathological STXBP1 variants are reported, with little genotypic‐phenotypic correlation (Lanoue et al., 2019). This suggested that pathology primarily arises from a loss of function and STXBP1 haploinsufficiency (Yamamoto et al., 2016).…”

“…Furthermore, expression of human mutants in Stxbp1 heterozygous neurons results in greatly reduced total munc‐18 levels, exceeding that expected from loss of mutant protein alone (Chai, Sierecki, & Tomatis, 2016; Guiberson et al., 2018; Kovačević et al., 2018; Patzke et al., 2015). This is proposed to reflect a gain of function pathology that is associated with an aggregation of STXBP1 mutants with remaining wild‐type protein (Lanoue et al., 2019). When common pathological STXBP1 variants were expressed in either Stxbp1 knockout mouse neurons or were added to an in vitro fusion assay, impaired neurotransmission or defective SNARE‐dependent membrane fusion were respectively observed (Guiberson et al., 2018; Kovačević et al., 2018; Shen et al., 2015).…”