Tadashi Nakagawa

Neurodevelopmental disorders (NDDs) comprise a genetically and clinically heterogeneous group of conditions, with disruption of chromatin regulation and developmental gene-expression programs representing an important molecular mechanism underlying their pathogenesis. SET domain-containing (SETD) proteins constitute a diverse family of chromatin regulators that primarily mediate histone methylation, although some lack demonstrated intrinsic catalytic activity or modify non-histone substrates. Pathogenic variants in multiple SETD genes, including SETD1A, KMT2D, SETD2, NSD1, and EZH2, cause NDDs characterized by developmental delay, intellectual disability, speech and language impairment, autism-related features, epilepsy, growth abnormalities, and congenital anomalies. Representative examples include SETD1A-related neurodevelopmental disorder (OMIM #619056), KMT2D-related Kabuki syndrome type 1 (OMIM #147920), SETD2-related Luscan–Lumish syndrome (OMIM #616831), NSD1-related Sotos syndrome (OMIM #117550), and EZH2-related Weaver syndrome (OMIM #277590). In this review, we summarize the classification, domain architecture, and molecular functions of human SETD proteins and integrate clinical findings with mechanistic insights obtained from genetically modified mouse models. These studies reveal substantial cross-species convergence in cognitive, behavioral, synaptic, and developmental phenotypes while also demonstrating that individual SETD proteins regulate distinct molecular processes. Importantly, phenotypic similarity does not necessarily indicate a common molecular mechanism, and variant-specific effects, including loss-of-function, gain-of-function, dominant-negative, and substrate-selective alterations, must be considered when interpreting experimental models. Several studies further demonstrate partial reversibility of molecular and behavioral abnormalities through restoration of SETD protein function, inhibition of opposing chromatin-modifying enzymes such as LSD1, or correction of downstream signaling pathways. These findings suggest that therapeutic opportunities may extend beyond transcriptional regulation to downstream processes including translation, synaptic function, and cellular signaling. Integrating human genetics with animal and human cellular models will therefore be essential for defining shared and gene-specific mechanisms and identifying therapeutically actionable pathways in SETD-related NDDs.

Protein ubiquitylation plays fundamental roles in virtually every aspect of eukaryotic cellular function by regulating the stability and activity of target proteins

Neurodevelopmental disorders (NDDs) are characterized by remarkable phenotypic heterogeneity, in which individuals harboring mutations in the same gene display divergent clinical manifestations, ranging from mild cognitive impairment to severe neurodevelopmental deficits. Advances in neurogenetics and neurogenomics have rapidly expanded the catalog of genes associated with NDDs and have provided unprecedented insight into the genetic architecture of these conditions. However, how identical or similar genetic variants give rise to such diverse phenotypic outcomes remains largely unknown. Ubiquitin-mediated protein regulation is a central mechanism controlling diverse processes essential for neural development, including chromatin regulation, transcriptional dynamics, protein turnover, and synaptic function. Importantly, ubiquitination is a multilayered regulatory process governed by multiple determinants, including the availability of ubiquitination sites on substrates, the activity of ubiquitin ligases, the opposing actions of deubiquitinases, and priming post-translational modifications such as phosphorylation or acetylation. These regulatory layers create a dynamic ubiquitination landscape that may vary across individuals, cell types, developmental stages, and environmental contexts. In this review, we discuss how insights from neurogenetics and neurogenomics can be integrated with knowledge of ubiquitin signaling to better understand the molecular basis of phenotypic heterogeneity in NDDs. We propose that differential ubiquitination represents an important mechanistic framework through which genetic variation is translated into diverse molecular and cellular outcomes. Understanding the interplay between neurogenetic variation and ubiquitin-dependent regulatory networks may provide new perspectives on disease mechanisms and inform future therapeutic strategies for neurodevelopmental disorders.

Hydrogen sulfide (H ₂ S) functions as a signaling molecule and cytoprotectant. In many tissues, H ₂ S is produced from l ‐cysteine, whereas the kidney also produces H ₂ S from d ‐cysteine by the sequential activities of d ‐amino acid oxidase (DAO) and 3‐mercaptopyruvate sulfurtransferase (3MST). The d ‐cysteine pathway produces H ₂ S more efficiently than the l ‐cysteine pathway, and d ‐cysteine significantly reduces ischemia–reperfusion injury in the renal cortex compared with l ‐cysteine. However, the specific renal cell types responsible for the d ‐cysteine pathway have not been clearly identified. Here, we show that a subpopulation of MDCK (NBL‐2) cells, a renal epithelial cell line, expresses both DAO and 3MST. MDCK cells initially produced H ₂ S from d ‐cysteine, but this activity progressively declined with passage. In contrast, clonal cells expressing DAO and 3MST, established from this subpopulation, maintained stable H ₂ S production. The clonal cells exhibited two distinct patterns of DAO expression: one showed increased DAO levels after confluence, whereas the other displayed high DAO expression even before reaching confluence. These findings suggest that the d ‐cysteine pathway operates in epithelial cells and plays distinct roles depending on cellular state and dynamics. Moreover, the established clonal cells may provide insight into the role of d ‐cysteine‐mediated H ₂ S production in the kidney.

Neurodevelopmental disorders (NDDs) are characterized by remarkable phenotypic heterogeneity, in which individuals harboring mutations in the same gene display divergent clinical manifestations, ranging from mild cognitive impairment to severe neurodevelopmental deficits. Advances in neurogenetics and neurogenomics have rapidly expanded the catalog of genes associated with NDDs and have provided unprecedented insight into the genetic architecture of these conditions. However, how identical or similar genetic variants give rise to such diverse phenotypic outcomes remains largely unknown. Ubiquitin-mediated protein regulation is a central mechanism controlling diverse processes essential for neural development, including chromatin regulation, transcriptional dynamics, protein turnover, and synaptic function. Importantly, ubiquitination is a multilayered regulatory process governed by multiple determinants, including the availability of ubiquitination sites on substrates, the activity of ubiquitin ligases, the opposing actions of deubiquitinases, and priming post-translational modifications such as phosphorylation or acetylation. These regulatory layers create a dynamic ubiquitination landscape that may vary across individuals, cell types, developmental stages, and environmental contexts. In this review, we discuss how insights from neurogenetics and neurogenomics can be integrated with knowledge of ubiquitin signaling to better understand the molecular basis of phenotypic heterogeneity in NDDs. We propose that differential ubiquitination represents an important mechanistic framework through which genetic variation is translated into diverse molecular and cellular outcomes. Understanding the interplay between neurogenetic variation and ubiquitin-dependent regulatory networks may provide new perspectives on disease mechanisms and inform future therapeutic strategies for neurodevelopmental disorders.

Neurodevelopmental disorders (NDDs), including autism spectrum disorder, intellectual disability, and attention deficit hyperactivity disorder, are increasingly recognized as disorders of early brain construction arising from defects in neural stem and progenitor cell (NSPC) proliferation. NSPCs are responsible for generating the diverse neuronal and glial lineages that establish cortical architecture and neural circuitry; thus, their expansion must be tightly coordinated by intrinsic cell cycle regulators and extrinsic niche-derived cues. Disruption of these mechanisms—through genetic mutations, epigenetic dysregulation, or environmental insults—can perturb the balance between NSPC self-renewal and differentiation, resulting in aberrant brain size and connectivity. Recent advances using animal models and human pluripotent stem cell-derived brain organoids have identified key signaling pathways, including Notch, Wnt, SHH, and PI3K–mTOR, as central hubs integrating proliferative cues, while transcriptional and chromatin regulators such as PAX6, CHD8, SETD5, and ANKRD11 govern gene expression essential for proper NSPC cycling. Furthermore, prenatal exposure to teratogens such as Zika virus infection, valproic acid, or metabolic stress in phenylketonuria can recapitulate proliferation defects and microcephaly, underscoring the vulnerability of NSPCs to environmental perturbation. This review summarizes emerging insights into the molecular and cellular mechanisms by which defective NSPC proliferation contributes to NDD pathogenesis, highlighting convergence among genetic and environmental factors on cell cycle control. A deeper understanding of these pathways may uncover shared therapeutic targets to restore neurodevelopmental trajectories and mitigate disease burden.

Neurodevelopmental disorders (NDDs), including autism spectrum disorder, intellectual disability, and attention deficit hyperactivity disorder, are increasingly recognized as disorders of early brain construction arising from defects in neural stem and progenitor cell (NSPC) proliferation. NSPCs are responsible for generating the diverse neuronal and glial lineages that establish cortical architecture and neural circuitry; thus, their expansion must be tightly coordinated by intrinsic cell cycle regulators and extrinsic niche-derived cues. Disruption of these mechanisms—through genetic mutations, epigenetic dysregulation, or environmental insults—can perturb the balance between NSPC self-renewal and differentiation, resulting in aberrant brain size and connectivity. Recent advances using animal models and human pluripotent stem cell–derived brain organoids have identified key signaling pathways, including Notch, Wnt, SHH, and PI3K–mTOR, as central hubs integrating proliferative cues, while transcriptional and chromatin regulators such as PAX6, CHD8, SETD5, and ANKRD11 govern gene expression essential for proper NSPC cycling. Furthermore, prenatal exposure to teratogens such as Zika virus infection, valproic acid, or metabolic stress in phenylketonuria can recapitulate proliferation defects and microcephaly, underscoring the vulnerability of NSPCs to environmental perturbation. This review summarizes emerging insights into the molecular and cellular mechanisms by which defective NSPC proliferation contributes to NDD pathogenesis, highlighting convergence among genetic and environmental factors on cell cycle control. A deeper understanding of these pathways may uncover shared therapeutic targets to restore neurodevelopmental trajectories and mitigate disease burden.

Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disorder characterized by the progressive degeneration of motor neurons, leading to muscle weakness, paralysis, and death. Although significant progress has been made in understanding ALS, its molecular mechanisms remain complex and multifactorial. This review explores the potential convergent mechanisms underlying ALS pathogenesis, focusing on the roles of key proteins including NEK1, C21ORF2, cyclin F, VCP, and TDP-43. Recent studies suggest that mutations in C21ORF2 lead to the stabilization of NEK1, while cyclin F mutations activate VCP, resulting in TDP-43 aggregation. TDP-43 aggregation, a hallmark of ALS, impairs RNA processing and protein transport, both of which are essential for neuronal function. Furthermore, TDP-43 has emerged as a key player in DNA damage repair, translocating to DNA damage sites and recruiting repair proteins. Given that NEK1, VCP, and cyclin F are also involved in DNA repair, this review examines how these proteins may intersect to disrupt DNA damage repair mechanisms, contributing to ALS progression. Impaired DNA repair and protein homeostasis are suggested to be central downstream mechanisms in ALS pathogenesis. Ultimately, understanding the interplay between these pathways could offer novel insights into ALS and provide potential therapeutic targets. This review aims to highlight the emerging connections between protein aggregation, DNA damage repair, and cellular dysfunction in ALS, fostering a deeper understanding of its molecular basis and potential avenues for intervention.

Ubiquitination is a dynamic and tightly regulated post-translational modification essential for modulating protein stability, trafficking, and function to preserve cellular homeostasis. This process is orchestrated through a hierarchical enzymatic cascade involving three key enzymes: the E1 ubiquitin-activating enzyme, the E2 ubiquitin-conjugating enzyme, and the E3 ubiquitin ligase. The final step of ubiquitination is catalyzed by the E3 ubiquitin ligase, which facilitates the transfer of ubiquitin from the E2 enzyme to the substrate, thereby dictating which proteins undergo ubiquitination. Emerging evidence underscores the critical roles of ubiquitin ligases in neurodevelopment, regulating fundamental processes such as neuronal polarization, axonal outgrowth, synaptogenesis, and synaptic function. Mutations in genes encoding ubiquitin ligases and the consequent dysregulation of these pathways have been increasingly implicated in a spectrum of neurodevelopmental disorders, including autism spectrum disorder, intellectual disability, and attention-deficit/hyperactivity disorder. This review synthesizes current knowledge on the molecular mechanisms underlying neurodevelopment regulated by Cullin-RING ubiquitin ligases—the largest subclass of ubiquitin ligases—and their involvement in the pathophysiology of neurodevelopmental disorders. A deeper understanding of these mechanisms holds significant promise for informing novel therapeutic strategies, ultimately advancing clinical outcomes for individuals affected by neurodevelopmental disorders.