Irina Dudanova

Max Planck Institute of Neurobiology

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Rüdiger Klein

Max Planck Institute for Biological Intelligence

F. Ulrich Hartl

Max Planck Institute of Biochemistry

Mark S. Hipp

University Medical Center Groningen

Wolfgang Baumeister

Max Planck Institute of Biochemistry

Rubén Fernández‐Busnadiego

University of Göttingen

Victoria A. Trinkaus

Max Planck Institute of Biochemistry

Qiang Guo

Peking University

Itika Saha

Max Planck Institute of Biochemistry

Marc I. Diamond

The University of Texas Southwestern Medical Center

Hauke Holthusen

Max Planck Institute of Biochemistry

Cooperative Institutions

Max Planck Institute of Neurobiology

Max Planck Institute of Biochemistry

Max Planck Society

University Medical Center Groningen

University of Groningen

Carl von Ossietzky Universität Oldenburg

University of Göttingen

Max Planck Institute for Biological Intelligence

Stanford University

Munich Cluster for Systems Neurology

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Optogenetic restoration of neuron subtype-specific cortical activity ameliorates motor deficits in Huntington′s Disease mice

bioRxiv (Cold Spring Harbor Laboratory) (2025)

Sonja Blumenstock David Arakelyan Nicholas del Grosso Sabine Schneider Yufeng Shao

Abstract Huntington’s disease (HD) is a devastating movement disorder without a current cure. Although the monogenic basis of HD is well-defined, the complex downstream effects that underlie behavioral symptoms are poorly understood. These effects include cortical dysfunctions, yet the role of specific cortical neuronal subtypes in HD symptoms remain largely unexplored. Here, we used longitudinal in vivo two-photon calcium imaging to examine the activity of two cortical inhibitory neuron (IN) subtypes and excitatory corticostriatal projection neurons (CSPNs) in the motor cortex of R6/2 HD mouse model throughout disease progression. We found that motor deficits in R6/2 mice were accompanied by neuron type-specific abnormalities in movement-related activity, including hypoactivity of vasoactive intestinal peptide (VIP)-INs and CSPNs. Optogenetic activation of VIP-INs in R6/2 mice restored healthy levels of activity in VIP-INs and their downstream CSPNs and ameliorated motor deficits in R6/2 mice. Our findings highlight cortical INs as a potential therapeutic target for HD and possibly other neurological diseases.

Cortical neurons

10.1101/2025.02.07.637155

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The Axon's Balancing Act: cis- and trans-Interactions between Ephs and Ephrins

Neuron (2011)

Irina Dudanova Rüdiger Klein

Ephrin

10.1016/j.neuron.2011.06.030

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Citations (21)

Detection of Tau ubiquitylation v1

Itika Saha F. Ulrich Hartl Mark S. Hipp Felix Kraus Patricia Yuste- Checa

This protocol describes the detection of ubiquitylated Tau from HEK293 cells stably expressing and propagating aggregates of Tau repeat domain fused to YFP (Sanders et al. Neuron, 2014; Saha et al, BioRxiv, 2022).

HEK 293 cells

10.17504/protocols.io.3byl4je4rlo5/v1

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Lentivirus production v1

Itika Saha F. Ulrich Hartl Mark S. Hipp Felix Kraus Patricia Yuste- Checa

This protocol describes the production of lentiviruses to transduce HEK293T cells and has to be performed in a biosafety level 2 laboratory

10.17504/protocols.io.6qpvr4xn3gmk/v1

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Novel proteostasis reporter mouse reveals different effects of cytoplasmic and nuclear aggregates on protein quality control in neurons

bioRxiv (Cold Spring Harbor Laboratory) (2020)

Sonja Blumenstock Elena Katharina Schulz‐Trieglaff Anna‐Lena Bolender Kerstin Voelkl Paul Lapios

Abstract The cellular protein quality control machinery is important for preventing protein misfolding and aggregation, and decline in protein homeostasis (proteostasis) is believed to play a crucial role in age-related neurodegenerative disorders. However, how proteostasis capacity of neurons changes in different diseases is not yet sufficiently understood, and progress in this area has been hampered by the lack of tools to monitor proteostasis in mammalian models. Here, we have developed reporter mice for in vivo analysis of neuronal proteostasis. The mice express EGFP-fused firefly luciferase (Fluc), a conformationally unstable protein that requires chaperones for proper folding and sensitively reacts to proteotoxic stress by formation of intracellular Fluc-EGFP foci and by reduced luciferase activity. Using these mice, we provide evidence for proteostasis decline in the aging brain. Moreover, we find a marked impairment in proteostasis in tauopathy mice, but not in Huntington’s disease mice. Mechanistic investigations in primary neuronal cultures demonstrate that cytoplasmic, but not nuclear, aggregates cause defects of cellular protein quality control. Thus, the Fluc-EGFP reporter mice enable new insights into proteostasis alterations in different diseases.

Proteostasis

10.1101/2020.11.09.374231

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Balancing neuronal circuits

Science (2022)

Sonja Blumenstock Irina Dudanova

Correcting synaptic defects in development delays Huntington's disease symptoms in older mice.

Neuronal Circuits

10.1126/science.ade3116

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Deletion of α‐neurexins does not cause a major impairment of axonal pathfinding or synapse formation

The Journal of Comparative Neurology (2007)

Irina Dudanova Katsuhiko Tabuchi Astrid Rohlmann Thomas C. Südhof Markus Missler

Abstract α‐Neurexins are synaptic cell‐surface molecules that are required for Ca 2+ ‐triggered exocytosis. Mice lacking all three α‐neurexins show drastically reduced neurotransmitter release at excitatory and inhibitory synapses and die early postnatally. Although previous histological analysis of newborn α‐neurexin triple mutants revealed only a moderate reduction in the density of type II synapses in the brainstem, cell culture studies proposed that neurexins are prominently involved in synapse formation. To assess the contribution of α‐neurexins to the formation and structural properties of synapses in vivo, we performed a detailed morphological analysis of the brains from surviving adult double knockout mice lacking two of the three α‐neurexins. Despite their impaired neurotransmission, we did not observe any gross anatomical defects or changes in the distribution of synaptic proteins in adult mutants. Only mild structural alterations were found: a ∼20% reduction of neuropil area in many brain regions, resulting predominantly from shortened distal dendritic branches and fewer spines, as demonstrated by Golgi impregnation of pyramidal neurons. Quantitative electron microscopy revealed ultrastructurally normal type I and II terminals and a ∼30% decrease in the density of type II synapses in the neocortex. To exclude errors in pathfinding, we investigated axonal projections in the olfactory bulb of newborn knockouts and did not observe any changes. Therefore, α‐neurexins are not essential for the formation of the vast majority of synapses in vivo but rather regulate the function of these synapses. J. Comp. Neurol. 502:261–274, 2007. © 2007 Wiley‐Liss, Inc.

Neuropil

Neocortex

Neuroligin

10.1002/cne.21305

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Citations (98)

Cortical circuit alterations precede disease onset in Huntington’s disease mice

bioRxiv (Cold Spring Harbor Laboratory) (2018)

Johanna Neuner Elena Katharina Schulz‐Trieglaff Sara Gutiérrez-Ángel Fabian Hosp Matthias Mann

Abstract Huntington’s disease (HD) is a devastating hereditary movement disorder, characterized by degeneration of neurons in the striatum and cortex. Studies in human patients and mouse HD models suggest that disturbances of neuronal function in the neocortex play an important role in the disease onset and progression. However, the precise nature and time course of cortical alterations in HD have remained elusive. Here, we use chronic in vivo two-photon calcium imaging to monitor the activity of single neurons in layer 2/3 of the primary motor cortex in awake, behaving R6/2 transgenic HD mice and wildtype littermates. R6/2 mice show age-dependent changes in neuronal activity with a clear increase in activity at the age of 8.5 weeks, preceding the onset of motor and neurological symptoms. Furthermore, quantitative proteomics demonstrate a pronounced downregulation of synaptic proteins in the cortex, and histological analyses in R6/2 mice and HD patient samples reveal reduced inputs from parvalbumin-positive interneurons onto layer 2/3 pyramidal cells. Thus, our study provides a time-resolved description as well as mechanistic details of cortical circuit dysfunction in HD. Significance statement Funtional alterations in the cortex are believed to play an important role in the pathogenesis of Huntington’s disease (HD). However, studies monitoring cortical activity in HD models in vivo at a single-cell resultion are still lacking. We have used chronic two-photon imaging to investigate changes in the activity of single neurons in the primary motor cortex of awake presymptomatic HD mice. We show that neuronal activity increases before the mice develop disease symptoms. Our histological analyses in mice and in human HD autopsy cases furthermore demonstrate a loss inhibitory synaptic terminals from parvalbimun-positive interneurons, revealing a potential mechanism of cortical circuit impairment in HD.

Neocortex

Pathogenesis

Calcium imaging

10.1101/391771

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The extracellular chaperone Clusterin enhances Tau aggregate seeding in a cellular model

Nature Communications (2021)

Patricia Yuste‐Checa Victoria A. Trinkaus Irene Riera-Tur Rahmi Imamoglu Theresa Schaller

Abstract Spreading of aggregate pathology across brain regions acts as a driver of disease progression in Tau-related neurodegeneration, including Alzheimer’s disease (AD) and frontotemporal dementia. Aggregate seeds released from affected cells are internalized by naïve cells and induce the prion-like templating of soluble Tau into neurotoxic aggregates. Here we show in a cellular model system and in neurons that Clusterin, an abundant extracellular chaperone, strongly enhances Tau aggregate seeding. Upon interaction with Tau aggregates, Clusterin stabilizes highly potent, soluble seed species. Tau/Clusterin complexes enter recipient cells via endocytosis and compromise the endolysosomal compartment, allowing transfer to the cytosol where they propagate aggregation of endogenous Tau. Thus, upregulation of Clusterin, as observed in AD patients, may enhance Tau seeding and possibly accelerate the spreading of Tau pathology.

Clusterin

Chaperone (clinical)

Cellular model

10.1038/s41467-021-25060-1

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Citations (46)

Distinct histological alterations of cortical interneuron types in mouse models of Huntington’s disease

Frontiers in Neuroscience (2022)

Kerstin Voelkl Elena Katharina Schulz‐Trieglaff Rüdiger Klein Irina Dudanova

Huntington's disease (HD) is a debilitating hereditary motor disorder caused by an expansion of the CAG triplet repeat in the Huntingtin gene. HD causes neurodegeneration particularly in the basal ganglia and neocortex. In the cortex, glutamatergic pyramidal neurons are known to be severely affected by the disease, but the involvement of GABAergic interneurons remains unclear. Here, we use a combination of immunostaining and genetic tracing to investigate histological changes in three major cortical interneuron types - parvalbumin (PV), somatostatin (SST), and vasoactive intestinal peptide (VIP) interneurons - in the R6/2 and zQ175DN mouse models of HD. In R6/2 mice, we find a selective reduction in SST and VIP, but not PV-positive cells. However, genetic labeling reveals unchanged cell numbers for all the interneuron types, pointing to molecular marker loss in the absence of cell death. We also observe a reduction in cell body size for all three interneuron populations. Furthermore, we demonstrate progressive accumulation of mutant Huntingtin (mHTT) inclusion bodies in interneurons, which occurs faster in SST and VIP compared to PV cells. In contrast to the R6/2 model, heterozygous zQ175DN knock-in HD mice do not show any significant histological changes in cortical cell types at the age of 12 months, apart from the presence of mHTT inclusions, which are abundant in pyramidal neurons and rare in interneurons. Taken together, our findings point to differential molecular changes in cortical interneuron types of HD mice.

Interneuron

Neocortex

10.3389/fnins.2022.1022251

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Citations (1)