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Results for “Translational neurogenetics”

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6 recordsLinked to original sources

PubMed2026

A novel iPSC model of Bryant-Li-Bhoj neurodevelopmental/neurodegenerative syndrome demonstrates the role of histone H3.3 in chromatin dynamics, neuronal differentiation, and maturation.

BACKGROUND: Bryant-Li-Bhoj neurodevelopmental syndrome (BLBS) is neurogenetic disorder caused by variants in H3-3A and H3-3B, the two genes that encode histone H3.3. Ninety-nine percent of individuals with BLBS show developmental delay/intellectual disability, but the mechanism by which variants in H3.3 result in these phenotypes is not yet understood, limiting the therapeutic interventions available to individuals living with BLBS. METHODS: Here, we investigate how one BLBS-causative variant, H3-3B p.Leu48Arg (L48R), affects neurodevelopment using an induced pluripotent stem cell model differentiated to 2D neural progenitor cells (NPCs), 2D forebrain neurons (FBNs), and 3D dorsal forebrain organoids (DFBOs). We employ a multi-omic approach in the 2D models to quantify the resulting changes in gene expression and chromatin accessibility. We used immunofluorescence (IF) staining to define the identities of cells in the 3D DFBOs and whole-cell patch clamp to investigate the electrophysiological properties of neurons in DFBOs. RESULTS: In the 2D systems, we found dysregulated gene expression and chromatin accessibility affecting neuronal fate, adhesion, neurotransmission, and excitatory/inhibitory balance. Immunofluorescence of DFBOs corroborated altered proportions of radial glia and mature neuronal populations. Patch clamp recordings revealed decreased electrical activity in neurons from L48R DFBOs compared to control DFBOs. CONCLUSIONS: These data provide the first mechanistic insights into the pathogenesis of BLBS from a human-derived model of neurodevelopment, which suggest that H3.3 L48R increases H3-3B expression, resulting in the hyper-deposition of H3.3 into the nucleosome, which underlies changes in gene expression and chromatin accessibility. Functionally, this causes dysregulation of cell adhesion, neurotransmission, and the balance between excitatory and inhibitory signaling. These results are a crucial step towards preclinical development and testing of targeted therapies for this and related disorders.

Histones↗

PubMed1998

Craniocerebral trauma: protection and retrieval of the neuronal population after injury.

OBJECTIVE: To review the consequences of mechanical injury to the brain with an emphasis on factors that may explain the variability of outcomes and how this might be influenced. METHODS: Information regarding the pathophysiology of traumatic brain damage contained in original scientific reports and in review articles published in recent years was reviewed from the perspective of a clinical neurosurgeon and a neuropathologist, each with major research interests in traumatic brain damage. The information was compiled on the basis of the knowledge of and personal selection of articles that were identified through selective literature searches and current awareness profiles. A systematic literature review was not conducted. RESULTS: Mechanical input affects neuronal and vascular elements and is translated into biological effects on the brain through a complex series of interacting cellular and molecular events. Whether these lead to permanent structural damage or to resolution and recovery is determined by the balance between processes that, on the one hand, mediate the effects of initial injury and subsequent secondary insults and, on the other, are manifestations of the brain's protective, reparative response. Experimental and clinical research has identified opportunities for altering the balance in a way that might promote recovery, but data demonstrating that this can lead to substantial clinical benefit are lacking. Recent evidence of genetically determined, individual susceptibility to the effects of injury may explain some of the puzzling variability in outcome after apparently similar insults and may also provide new opportunities for treatment. CONCLUSION: The understanding of traumatic brain damage that is being gained from recent research is widening and broadening perspectives from the traditional focus on mechanical, vascular, and metabolic effects to encompass wider, neurobiological issues, drawn from the fields of neurodevelopment, neuroplasticity, neurodegeneration, and neurogenetics. Neurotrauma is a fascinating area of neuroscience research, with promise for the translation of knowledge to improved clinical management and outcome.

Animals↗

PubMed2006

The genetics of Parkinson disease: Implications for neurological care.

The identification of single genes linked to heritable forms of Parkinson disease (PD) has challenged the previously held view of a nongenetic etiology for this progressive movement disorder. Detailed analyses of individuals with mutations in SNCA, Parkin, PINK1, DJ1 or LRRK2 have greatly advanced our knowledge of preclinical and clinical, morphological, and pathological changes in PD. These genetic breakthroughs have had profound implications for scientists, neurologists and patients alike. Such advances have provided unique opportunities to pursue the mechanisms of neuronal degeneration in models of PD pathogenesis, thereby reinforcing the significance of oxidative stress and mitochondrial dysfunction. With emerging clues from familial variants, researchers have begun to explore factors that lead to the expression of the more common, sporadic disease phenotype (idiopathic PD), including interactions between various genes, modifying effects of susceptibility alleles and epigenetic factors, and the influence of environmental agents and aging on the expression of PD-linked genes. These genetic leads have added to the urgency of developing translational drug treatments, and neurologists and their patients are confronting considerations relating to DNA testing. In this article, we summarize recent progress in establishing a neurogenetic component of PD, emphasize the need for developing PD biomarkers to improve diagnostic accuracy (in both clinical practice and therapeutic trials), and discuss scenarios in which specific DNA tests might be considered for diagnostic purposes. In the absence of consensus guidelines for DNA testing in PD and of any neuroprotective treatment for this nonfatal disorder, we remind ourselves of the omnipresent mandate, 'Primum nil nocere!' ('First, do no harm!').

Genes, Dominant↗

PubMed2001

Distinct multi-joint control strategies in spastic diplegia associated with prematurity or Angelman syndrome.

Spastic diplegia is commonly due to periventricular leucomalacia associated with premature birth. It is also a feature of Angelman syndrome (AS), a neurogenetic disorder with developmental delay, absent speech and mirthful behaviour. We studied the kinematics and kinetics of the squatting movement and associated electromyographic (EMG) activities in 20 children with spastic diplegia associated with periventricular leucomalacia (SDPL) or AS and 18 unimpaired children. While movement of normal subjects consisted of vertical translation of most body segments, the movement of SDPL children was operated around the fixed knee with backward shift of the hip, and AS children performed a forward flexion of the trunk over the thigh. Trunk stability was correlated with movement velocity in both pathological groups. In normal subjects, anticipatory EMG pattern consisted of silencing of hamstring muscle tonic activity prior to movement onset. This deactivation was not present in spastic diplegia. In SDPL, anticipatory overactivation of ankle joint actuators was recorded and tonic co-contraction persisted throughout the movement. In AS, rhythmic EMG bursting was seen during the movement. Shoulder, hip and knee trajectories in the sagittal plane showed marked within-group stereotypies in orientation, shape and length. The patterns in both pathological groups were therefore distinctive. We speculate that they reflect corticospinal impairment in SDPL and combined corticospinal and cerebellar dysfunction in AS.

Angelman Syndrome↗

PubMed2004

Molecular pathophysiology of mucolipidosis type IV: pH dysregulation of the mucolipin-1 cation channel.

Mucolipidosis type IV (MLIV) is an autosomal recessive neurogenetic disorder characterized by developmental abnormalities of the brain and impaired neurological, ophthalmologic and gastric function. Large vacuoles accumulate in various types of cells in MLIV patients. However, the pathophysiology of the disease at the cellular level is still unknown. MLIV is caused by mutations in a recently described gene, MCOLN1, encoding mucolipin-1 (ML1), a 65 kDa protein whose function is also unknown. ML1 shows sequence homology and topological similarities with polycystin-2 and other transient receptor potential (Trp) channels. In this study, we assessed both, whether ML1 has ion channel properties, and whether disease-causing mutations in MCOLN1 have functional differences with the wild-type (WT) protein. ML1 channel function was assessed from endosomal vesicles of null (MCOLN1(-/-)) and ML1 over-expressing cells, and liposomes containing the in vitro translated protein. Evidence from both preparations indicated that WT ML1 is a multiple subconductance non-selective cation channel whose function is inhibited by a reduction of pH. The V446L and DeltaF408 MLIV causing mutations retain channel function but not the sharp inhibition by lowering pH. Atomic force imaging of ML1 channels indicated that changes in pH modified the aggregation of unitary channels. Mutant-ML1 did not change in size on reduction of pH. The data indicate that ML1 channel activity is regulated by a pH-dependent mechanism that is deficient in some MLIV causing mutations of the gene. The evidence also supports a novel role for cation channels in the acidification and normal endosomal function.

Cells, Cultured↗

PubMed2026

Prader-Willi syndrome as a neurogenetic model for psychosis and obsessive-compulsive disorder: A review of clinical, behavioral, and biological insights.

Prader-Willi syndrome (PWS) is a complex neurodevelopmental disorder classically defined by hyperphagia and obesity. However, its profound psychiatric phenotype offers a unique genetic framework for understanding major mental illnesses. This review positions PWS as a potentially informative biological model for psychosis and obsessive-compulsive disorder (OCD), bridging the gap between 15q11-q13 imprinting defects and neural circuit dysfunction. We synthesize evidence demonstrating that psychosis in PWS is not a uniform trait but is disproportionately linked to the maternal uniparental disomy (mUPD) subtype. This genotype-phenotype correlation suggests that overexpression of maternally imprinted genes and loss of paternal expression disrupt cortical excitatory-inhibitory balance, resembling the "schizophrenia-bipolar" genomic architecture. Furthermore, synthesized evidence characterizes the repetitive, ritualistic behaviors in PWS not merely as behavioral challenges, but as a developmentally arrested OCD-spectrum phenotype driven by distinct serotonergic-oxytocinergic imbalances and hypothalamic-limbic dysconnectivity. Mechanistic insights from preclinical models of MAGEL2, SNORD116, and NDN deficiency are integrated with clinical findings to highlight shared neurobiological substrates. Finally, we outline a roadmap for precision psychiatry in PWS, emphasizing the necessity of pharmacogenomics in antipsychotic management and the potential of targeted circuit-based therapeutics. By deconstructing the psychiatric comorbidities of PWS, we provide a framework for translating genomic architecture into mechanistic understanding and targeted treatment for complex neuropsychiatric disorders.

15q11-q13↗