A novel mouse model reproducing frontal alterations related to the prodromal stage of dementia with LEWY bodies.

BACKGROUND: Dementia with Lewy bodies (DLB) is the second most common age-related neurocognitive pathology after Alzheimer's disease. Animal models characterizing this disease are lacking and their development would ameliorate both the understanding of neuropathological mechanisms underlying DLB as well as the efficacy of pre-clinical studies tackling this disease. METHODS: We performed extensive phenotypic characterization of a transgenic mouse model overexpressing, most prominently in the dorsal hippocampus (DH) and frontal cortex (FC), wild-type form of the human α-synuclein gene (mThy1-hSNCA, 12 to 14-month-old males). Moreover, we drew a comparison of our mouse model results to DH- and FC- dependent neuropsychological and neuropathological deficits observed in a cohort of patients including 34 healthy control subjects and 55 prodromal-DLB patients (males and females). RESULTS: Our study revealed an increase of pathological form of soluble α-synuclein, mainly in the FC and DH of the mThy1-hSNCA model. However, functional impairment as well as increase in transcripts of inflammatory markers and decrease in plasticity-relevant protein level were exclusive to the FC. Furthermore, we did not observe pathophysiological or Tyrosine Hydroxylase alterations in the striatum or substantia nigra, nor motor deficits in our model. Interestingly, the results stemming from the cohort of prodromal DLB patients also demonstrated functional deficits emanating from FC alterations, along with preservation of those usually related to DH dysfunctions. CONCLUSIONS: This study demonstrates that pathophysiological impairment of the FC with concomitant DH preservation is observed at an early stage of DLB, and that the mThy1-hSNCA mouse model parallels some markers of this pathology.

Molecular and Phenotypic Characterization of the RORB-Related Disorder.

BACKGROUND AND OBJECTIVES: Heterozygous variants in RAR-related orphan receptor B (RORB) have recently been associated with susceptibility to idiopathic generalized epilepsy. However, few reports have been published so far describing pathogenic variants of this gene in patients with epilepsy and intellectual disability (ID). In this study, we aimed to delineate the epilepsy phenotype associated with RORB pathogenic variants and to provide arguments in favor of the pathogenicity of variants. METHODS: Through an international collaboration, we analyzed seizure characteristics, EEG data, and genotypes of a cohort of patients with heterozygous variants in RORB. To gain insight into disease mechanisms, we performed ex vivo cortical electroporation in mouse embryos of 5 selected variants, 2 truncating and 3 missense, and evaluated on expression and quantified changes in axonal morphology. RESULTS: We identified 35 patients (17 male, median age 10 years, range 2.5-23 years) carrying 32 different heterozygous variants in RORB, including 28 single-nucleotide variants or small insertions/deletions (12 missense, 12 frameshift or nonsense, 2 splice-site variants, and 2 in-frame deletions), and 4 microdeletions; de novo in 18 patients and inherited in 10. Seizures were reported in 31/35 (89%) patients, with a median age at onset of 3 years (range 4 months-12 years). Absence seizures occurred in 25 patients with epilepsy (81%). Nineteen patients experienced a single seizure type: absences, myoclonic absences, or absences with eyelid myoclonia and focal seizures. Nine patients had absence seizures combined with other generalized seizure types. One patient had presented with absences associated with photosensitive occipital seizures. Three other patients had generalized tonic-clonic seizures without absences. ID of variable degree was observed in 85% of the patients. Expression studies in cultured neurons showed shorter axons for the 5 tested variants, both truncating and missense variants, supporting an impaired protein function. DISCUSSION: In most patients, the phenotype of the RORB-related disorder associates absence seizures with mild-to-moderate ID. In silico and in vitro evaluation of the variants in our cohort, including axonal morphogenetic experiments in cultured neurons, supports their pathogenicity, showing a hypomorphic effect.