https://scholar.dgist.ac.kr/handle/20.500.11750/1205 2026-04-04T14:14:45Z https://scholar.dgist.ac.kr/handle/20.500.11750/59935 Title: Neuronal mitochondrial disaggregase CLPB ameliorates Huntington&apos;s disease pathology in mice Author(s): Kim, Hyeonho; Hyun, Gaeun; Kim, Seunghye; Yu, Changmo; Hong, Young-gi; Yu, Jihyeon; Bae, Sangsu; Rhee, Hyun-Woo; Ko, Jaewon; Um, Ji Won Abstract: Background: Huntington&apos;s disease (HD) is a devastating neurodegenerative disorder caused by CAG repeat expansion in the HTT gene, resulting in a polyglutamine-expanded huntingtin (HTT) protein that forms toxic aggregates. Although heat-shock proteins are known to facilitate the refolding or clearance of misfolded proteins, their precise role in modulating protein aggregation in HD remains unclear. Here, we explore the function of caseinolytic peptidase B (ClpB), a mitochondrial AAA+ ATPase and heat-shock protein, in maintaining proteostasis and synaptic integrity in HD. Methods: We examined how CLPB loss or overexpression in human embryonic kidney 293T (HEK293T) cells impacted the aggregation of wild-type HTT (HTT-Q23) and mutant HTT (HTT-Q79). In parallel, AAV-mediated ClpB knockdown or overexpression was applied to the striatum of HD model mice. and HTT aggregation and inhibitory synaptic alterations were assessed. Aggregate burden was quantified via immunostaining, and inhibitory synapse density was evaluated using VGAT immunohistochemistry and electrophysiological recordings. Results: In HEK293T cells, CLPB knockout led to abnormal aggregation of HTT-Q23 while CLPB overexpression reduced the size of HTT-Q79 aggregates. In the mouse striatum, ClpB knockdown increased HTT-Q23 aggregate numbers and altered HTT-Q79 aggregation morphology, whereas CLPB overexpression restored the density and size of VGAT-positive inhibitory synapses and improved inhibitory synaptic transmission in HD model mice. These effects of CLPB overexpression were associated with a reduced mitochondrial aggregation burden, suggesting that ClpB contributes to mitochondrial protein quality control. Conclusions: These results demonstrate that ClpB regulates both physiological and pathological HTT aggregation and contributes to maintaining inhibitory synaptic integrity. By modulating mitochondrial proteostasis, ClpB acts as a protective factor in HD pathology, highlighting its potential as a therapeutic target for neurodegenerative disorders characterized by protein misfolding. 2025-12-31T15:00:00Z https://scholar.dgist.ac.kr/handle/20.500.11750/59930 Title: MDGA2 homozygous loss-of-function variants cause developmental and epileptic encephalopathy Author(s): Morsy, H; Kim, H; Jang, G; Zaki, M.S.; Severino, M.; Abdelrazek, I.M.; Hussein, H.; Self, E.; Albaradie, R.S.; Bakur, K.; Firoozfar, Z.; Efthymiou, S.; Noureldeen, M.M.; Nabil, A.; Alvi, J.R.; Molavi, F.; Alavi, S.; Alibakhshi, R.; Topcu, V.; Mancilar, H.; Uctepe, E.; Yesilyurt, A.; Aldhalaan, H.; Tous, E.S.S.; Alhaddad, B.; Elbendary, H.M.; Scardamaglia, A.; Murphy, D.; Yepez, V.A.; Gagneur, J.; Omar, T.I.; Elmaksoud, M.A.; Vandrovocova, J.; Abdalla, E.; Reilly, M.M.; Sultan, T.; Alkuraya, F.S.; Gleeson, J.G.; Um, J.W.; Houlden, H.; Ko, Jaewon; Maarofian, R. Abstract: MDGA2 encodes a membrane-associated protein that is critical for regulating glutamatergic synapse development, modulating neuroligins (Nlgns), and maintaining excitatory-inhibitory synaptic balance. While MDGA2 functions have been extensively studied in murine and cellular models, its association with human developmental disorders has yet to be established. Through exome sequencing, we identified seven distinct homozygous loss-of-function variants in MDGA2 in nine individuals from seven consanguineous families, all presenting with developmental and epileptic encephalopathy (DEE). Clinically, these individuals exhibited a consistent phenotype including infantile hypotonia, severe neurodevelopmental delay, intractable seizures, along with distinct dysmorphic features. Neuroimaging findings included delayed/incomplete myelination, early-onset brain atrophy, white-matter thinning, basal ganglia volume loss, and small hippocampi. Functional studies of three representative nonsense variants revealed impaired MDGA2 membrane trafficking, disrupted Nlgn1 interaction, and perturbed MDGA2-mediated excitatory synaptic functions in mammalian expression systems and cultured hippocampal neurons. Our findings support the involvement of MDGA2 in a subtype of autosomal-recessive DEE. This not only underscores a loss-of-function pathogenic mechanism but also highlights the previously unrecognized role of MDGA2 in human synaptic development and regulation, significantly expanding our understanding of the genetic architecture of DEEs. 2026-01-31T15:00:00Z https://scholar.dgist.ac.kr/handle/20.500.11750/59926 Title: MDGAs as synaptic suppressors with implications in neurodevelopmental disorders Author(s): Ko, Jaewon Abstract: The MDGA family proteins, MDGA1 and MDGA2, are glycophosphatidylinositol (GPI)-anchored proteins with high expression in the central nervous system. Initially associated with neuronal migration, MDGAs also act as synaptic suppressors in postsynaptic neurons, where they interfere with functions of key synapse organizing proteins. Strikingly, the MDGAs act upon distinct extracellular binding proteins to negatively control different synaptic properties of diverse synapses and neural circuits. This review discusses recent research on MDGAs and highlights debates and unresolved questions to invigorate future research activities aimed at determining precisely how MDGAs modulate synaptic properties in the context of neural circuits. Given that MDGAs and their interacting proteins are strongly linked with various neurodevelopmental disorders, understanding how synaptic signaling pathways encompassing MDGA protein complexes will be instrumental for better understanding the pathophysiological mechanisms of associated brain disorders. 2025-11-30T15:00:00Z https://scholar.dgist.ac.kr/handle/20.500.11750/59925 Title: Paralogs of Slitrk cell adhesion molecules configure excitatory synapse specificity via distinct cellular mechanisms Author(s): Kim, Dongwook; Kim, Byeongchan; Kim, Jinhu; Seo, Na-Young; Kim, Hyeonho; Han, Kyung Ah; Yoon, Jubeen; Macks, Christian P.; de Wit, Joris; Sohn, Chang Ho; Lee, Kea Joo; Um, Ji Won; Ko, Jaewon Abstract: <Vertebrate neural circuit properties are shaped by synaptic cell adhesion molecules (CAMs). CAMs often have multiple paralogs but the possible redundancy of such paralogs remains underexplored. Using circuit-specific conditional knockout (cKO) mice deficient for Slitrk1 and Slitrk2, we show that these paralogs lack specific laminar expression in mature hippocampal neurons but divergently guide the specificity of neural circuits in distinct hippocampal subfields. Slitrk1 and Slitrk2 regulate distinct facets of excitatory synaptic properties in a microcircuit-dependent manner through binding to LAR-RPTPs, and additionally in the case of Slitrk2, through binding to PDZ domain-containing proteins and TrkB. Analyses of Slitrk2 V89M knock-in mice revealed that this schizophrenia-associated substitution acts uniquely as a loss-of-function mutation in some microcircuits to impair excitatory synaptic transmission, asynchronous release, and spatial reference memory. These findings demonstrate that even structurally and biochemically similar synaptic CAMs can play distinct roles in specifying neural circuit architecture. 2025-11-30T15:00:00Z