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Neuronal mitochondrial disaggregase CLPB ameliorates Huntington's disease pathology in mice

2026-02-05T08:40:12Z

Title: Neuronal mitochondrial disaggregase CLPB ameliorates Huntington'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'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.

MDGA2 homozygous loss-of-function variants cause developmental and epileptic encephalopathy

2026-02-05T08:40:15Z

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.

Paralogs of Slitrk cell adhesion molecules configure excitatory synapse specificity via distinct cellular mechanisms

2026-02-06T02:40:14Z

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:

CASKIN2 mediates PTPσ-orchestrated transsynaptic mechanisms at excitatory synapses

2026-02-05T06:10:10Z

Title: CASKIN2 mediates PTPσ-orchestrated transsynaptic mechanisms at excitatory synapses Author(s): Han, Kyung Ah; Jang, Gyubin; Lee, Hee-Yoon; Kim, Byeongchan; Kanato, Tayo; Vas, Virág; Buday, László; Liu, Xinran; Choi, Se-Young; Um, Ji Won; Ko, Jaewon Abstract: Presynaptic active zones (AZs) perform essential functions in orchestrating speedy and accurate neurotransmission. Despite extensive studies on their molecular constituents, it remains unclear how transsynaptic signals are organized at AZs. The two members of the CASKIN family of multidomain scaffold proteins, CASKIN1 and CASKIN2, bind to several AZ proteins and LAR receptor protein tyrosine phosphatases (LAR-RPTPs), and thus likely contribute to presynaptic assembly. Analysis using conditional knockout (cKO) mice deficient for CASKIN1 and/or -2 revealed that CASKIN2, but not CASKIN1, is critical for proper synaptic transmission, synaptic strength, and AZ protein arrangement at glutamatergic synapses. CASKIN1/2 deletion recapitulates Caskin2-cKO phenotypes. Strikingly, presynaptic CASKIN2 at hippocampal CA3 neurons specifically regulates postsynaptic N-methyl-D-aspartate receptor (NMDAR)-mediated responses, NMDAR surface expression, and long-term potentiation in CA1 pyramidal neurons. Moreover, PTPσ-mediated tyrosine dephosphorylation and multimerization of CASKIN2 are critical for the ability of CASKIN2 to regulate excitatory synaptic transmission, NMDAR functions, and activity-dependent presynaptic F-actin rearrangement. Last, the presence of CASKIN2 and PTPσ at Schaffer collateral circuits contributes to proper novel object location memory in mice. Our findings establish crucial roles of CASKIN2 in orchestrating LAR-RPTP-mediated transsynaptic NMDAR-related synaptic functions.