Essential role for InSyn1 in dystroglycan complex integrity and cognitive behaviors in mice

Uezu, Akiyoshi; Hisey, Erin; Kobayashi, Yoshihiko; Gao, Yudong; Bradshaw, Tyler Wa; Devlin, Patrick; Rodriguiz, Ramona M.; Tata, Purushothama Rao; Soderling, Scott H.

doi:10.7554/elife.50712

Cited by 24 publications

(17 citation statements)

References 106 publications

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“…The severe damage of the proteostasis of intracellular Atx3 may further influence its normal function. Similar case has also been reported that the normal function of Atx3 in stabilization of CREB-binding protein (CBP) may be destroyed by mutant Htt, and consequently lead to dysregulation of the CBP-related gene expression 56 . It is likely that the loss-of-function effect of Atx3 resulted from disruption of the cellular proteostasis may account for one of the pathologies in Huntington’s disease.…”

Section: Discussionsupporting

confidence: 66%

PolyQ-expanded proteins impair cellular proteostasis of ataxin-3 through sequestering the co-chaperone HSJ1 into aggregates

Yue

Hong

Zhang

et al. 2021

Sci Rep

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Polyglutamine (polyQ) expansion of proteins can trigger protein misfolding and amyloid-like aggregation, which thus lead to severe cytotoxicities and even the respective neurodegenerative diseases. However, why polyQ aggregation is toxic to cells is not fully elucidated. Here, we took the fragments of polyQ-expanded (PQE) ataxin-7 (Atx7) and huntingtin (Htt) as models to investigate the effect of polyQ aggregates on the cellular proteostasis of endogenous ataxin-3 (Atx3), a protein that frequently appears in diverse inclusion bodies. We found that PQE Atx7 and Htt impair the cellular proteostasis of Atx3 by reducing its soluble as well as total Atx3 level but enhancing formation of the aggregates. Expression of these polyQ proteins promotes proteasomal degradation of endogenous Atx3 and accumulation of its aggregated form. Then we verified that the co-chaperone HSJ1 is an essential factor that orchestrates the balance of cellular proteostasis of Atx3; and further discovered that the polyQ proteins can sequester HSJ1 into aggregates or inclusions in a UIM domain-dependent manner. Thereby, the impairment of Atx3 proteostasis may be attributed to the sequestration and functional loss of cellular HSJ1. This study deciphers a potential mechanism underlying how PQE protein triggers proteinopathies, and also provides additional evidence in supporting the hijacking hypothesis that sequestration of cellular interacting partners by protein aggregates leads to cytotoxicity or neurodegeneration.

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Section: Discussionsupporting

confidence: 66%

PolyQ-expanded proteins impair cellular proteostasis of ataxin-3 through sequestering the co-chaperone HSJ1 into aggregates

Yue

Hong

Zhang

et al. 2021

Sci Rep

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“…The rate of somatic mutation is high during neurogenesis at approximately 5.1 single-nucleotide variants per progenitor per day and pathogenic mutations during this period may cause malformations [ 7 , 17 ]. HTT is implicated in DNA repair and, if this is partially defective through HTT gene expansion, this could further increase the frequency of post-zygotic somatic mutations in neuronal precursors and lead to an increased occurrence of malformations in GEC [ 22 , 24 , 30 , 37 , 39 , 40 , 51 ].…”

Section: Discussionmentioning

confidence: 99%

Developmental malformations in Huntington disease: neuropathologic evidence of focal neuronal migration defects in a subset of adult brains

et al. 2021

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Neuropathologic hallmarks of Huntington Disease (HD) include the progressive neurodegeneration of the striatum and the presence of Huntingtin (HTT) aggregates that result from abnormal polyQ expansion of the HTT gene. Whether the pathogenic trinucleotide repeat expansion of the HTT gene causes neurodevelopmental abnormalities has garnered attention in both murine and human studies; however, documentation of discrete malformations in autopsy brains of HD individuals has yet to be described. We retrospectively searched the New York Brain Bank (discovery cohort) and an independent cohort (validation cohort) to determine whether developmental malformations are more frequently detected in HD versus non-HD brains and to document their neuropathologic features. One-hundred and thirty HD and 1600 non-HD whole brains were included in the discovery cohort and 720 HD and 1989 non-HD half brains were assessed in the validation cohort. Cases with developmental malformations were found at 6.4–8.2 times greater frequency in HD than in non-HD brains (discovery cohort: OR 8.68, 95% CI 3.48–21.63, P=4.8 × 10-5; validation cohort: OR 6.50, 95% CI 1.83–23.17, P=0.0050). Periventricular nodular heterotopias (PNH) were the most frequent malformations and contained HTT and p62 aggregates analogous to the cortex, whereas cortical malformations with immature neuronal populations did not harbor such inclusions. HD individuals with malformations had heterozygous HTT CAG expansions between 40 and 52 repeats, were more frequently women, and all were asymmetric and focal, aside from one midline hypothalamic hamartoma. Using two independent brain bank cohorts, this large neuropathologic series demonstrates an increased occurrence of developmental malformations in HD brains. Since pathogenic HTT gene expansion is associated with genomic instability, one possible explanation is that neuronal precursors are more susceptible to somatic mutation of genes involved in cortical migration. Our findings further support emerging evidence that pathogenic trinucleotide repeat expansions of the HTT gene may impact neurodevelopment.

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“…The localization of Dystroglycan to inhibitory synapses in forebrain pyramidal neurons has been described by multiple studies, while its function at these synapses has remained obscure (Brunig et al, 2002; Levi et al, 2002; Pribiag et al, 2014; Uezu et al, 2019). Recently, it was found that Dystroglycan is required for the function of CCK+ inhibitory basket synapses, but not PV+ basket synapses onto the same PyNs (Fruh et al, 2016).…”

Section: Discussionmentioning

confidence: 99%

“…In PyNs, Dystroglycan is highly concentrated on the cell body and proximal dendrites where it is a major postsynaptic component of inhibitory synapses ( Fig. 1A ; Brunig et al, 2002; Levi et al, 2002; Uezu et al, 2019; Zaccaria et al, 2001). However, because of its importance in early aspects of brain development, the role of Dystroglycan at synapses has remained obscure.…”

Section: Introductionmentioning

confidence: 99%

Neuronal Dystroglycan regulates postnatal development of CCK/cannabinoid receptor-1 interneurons

Miller

Wright

2021

Preprint

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The development of functional neural circuits requires the precise formation of synaptic connections between diverse neuronal populations. The molecular pathways that allow GABAergic interneuron subtypes in the mammalian brain to recognize their postsynaptic partners remain largely unknown. The transmembrane glycoprotein Dystroglycan is localized to inhibitory synapses in pyramidal neurons, where it is required for the proper function of CCK+ interneurons. We show that deletion of Dystroglycan from pyramidal neurons selectively impairs CCK+ interneuron development during the first postnatal week. In the absence of postsynaptic Dystroglycan, presynaptic CCK+ interneurons fail to elaborate their axons and largely disappear from the cortex, hippocampus, amygdala, and olfactory bulb. Bax deletion did not rescue CCK+ interneurons, suggesting that they are not eliminated by canonical apoptosis in Dystroglycan mutants. Rather, we observed an increase in CCK+ interneuron innervation of the striatum, suggesting that the remaining CCK+ interneurons re-directed their axons to neighboring areas where Dystroglycan expression remained intact. Together these findings identify Dystroglycan as a critical regulator of CCK+ interneuron development.

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Essential role for InSyn1 in dystroglycan complex integrity and cognitive behaviors in mice

Cited by 24 publications

References 106 publications

PolyQ-expanded proteins impair cellular proteostasis of ataxin-3 through sequestering the co-chaperone HSJ1 into aggregates

PolyQ-expanded proteins impair cellular proteostasis of ataxin-3 through sequestering the co-chaperone HSJ1 into aggregates

Developmental malformations in Huntington disease: neuropathologic evidence of focal neuronal migration defects in a subset of adult brains

Neuronal Dystroglycan regulates postnatal development of CCK/cannabinoid receptor-1 interneurons

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