Biology subjects

Kreutz, M. R.

Publications and source records attributed to Kreutz, M. R..

9 recordsLinked to original sources

bioRxiv2026

Cognitive impairments in a mouse model for Huntington's disease correlate with presymptomatic locomotion and number of CAG repeats

Huntingtons disease (HD) is a progressive neurodegenerative disorder caused by an expanded CAG repeat in the huntingtin (HTT) gene. The disease is characterized by movement disorders, and it also presents with personality changes, including apathy and aggression, along with cognitive decline. While most animal models for HD have been validated for motor deficits, less is known about alterations in other behavioral functions. Here, we performed a longitudinal study to analyze the behavior of a knock-in mouse model of HD with a chimeric mouse/human exon 1 containing 140 CAG repeats inserted in the murine huntingtin gene. We specifically inquired about the onset of cognitive impairments in knock-in mice and whether changes in various behavioral functions such as locomotion, anxiety, and cognition correlate at the individual level. Our data indicate that female and male knock-in mice exhibit reductions in body weight, novelty-induced locomotion, and remote spatial memory retrieval. However, social behavior, working, and short-term memory remain unaffected. Within knock-in mice, lower open-field activity correlated with poorer remote memory performance. Moreover, CAG repeat length negatively correlated with locomotor activity and spatial memory, indicating that greater repeat expansion predicts more severe behavioral impairment. These findings identify early affective changes, followed by selective long-term memory and locomotor deficits, in knock-in mice, supporting this model as a useful platform for studying prodromal HD and repeat-length-dependent disease variability. HighlightsO_LICAG140 knock-in mice show early anxiety, later reduced locomotion and memory deficits C_LIO_LILong-term and remote memory are impaired while short-term and working memory are spared C_LIO_LILower locomotion at the age of 8 months correlates with poorer memory at 14 months of age in individual CAG140 knock-in mice C_LIO_LIGreater CAG repeat length predicts worse locomotion and memory C_LI

animal behavior and cognition↗

bioRxiv2025

Activity-dependent control of axonal amphisome trafficking governs norepinephrine release in vivo

Amphisomes are autophagy-related organelles formed by the fusion of autophagosomes with late endosomes. In neurons, they contribute to both cargo degradation and signaling, yet their physiological roles in vivo remain unclear. Here, we show that axonal amphisome trafficking in highly branched locus coeruleus (LC) neurons is regulated by neuronal activity, novelty-associated behavioral state, and axonal norepinephrine (NE) signaling. Using fiber-mediated in vivo laser photoconversion and two-photon imaging, combined with chemogenetics and a genetically encoded norepinephrine sensor, we tracked amphisome transport in the intact brains. We show that organelles generated within distal LC axons projecting to the prefrontal and motor cortices (PFC/M1) undergo retrograde trafficking across the entire axonal length toward somatic compartments. Amphisome trafficking dynamics are bidirectionally regulated by presynaptic adrenergic signaling through opposing cAMP/PKA-dependent mechanisms. In vivo, elevated local autoreceptor-mediated norepinephrine signaling, involving association of activated {beta}2-adrenergic autoreceptors with SIPA1L2-positive amphisomes, constrains processive retrograde trafficking by promoting transient immobilization and localized, non-directional "jittery" motility states. Conversely, reduced local norepinephrine signaling promotes amphisome mobilization, and chemogenetic engagement of Gi-coupled signaling accelerated transport by reducing transient immobilization events and reinforcing directional processivity, thereby facilitating cargo delivery toward somatic degradative compartments. Together, these findings identify a local neuromodulatory mechanism linking norepinephrine signaling to axonal amphisome trafficking in vivo and suggest that neuromodulatory states, such as novelty- and wakefulness-associated LC activity, as well as sleep-associated silencing of LC activity, regulate neuronal proteostasis through local control of autophagic cargo transport.

neuroscience↗

bioRxiv2025

Amphisome biogenesis couples synaptic autophagy to local protein synthesis

Synaptic neurotransmission imposes high demands on membrane turnover, metabolism, and the remodeling of presynaptic molecular composition. While the impact of autophagy on neurotransmission has been firmly established, evidence for activity-dependent synaptic induction of autophagy remains surprisingly limited. Here, we demonstrate that amphisomes containing BDNF/TrkB are formed at presynaptic boutons following sustained synaptic activation. Activity-dependent bulk endocytosis serves as a membrane source for amphisome biogenesis, while key autophagy proteins are recruited to the active zone, and autophagy initiation is triggered locally by the energy-sensing kinase AMPK. BDNF/TrkB-containing amphisomes contribute to the turnover of key presynaptic cytoskeletal proteins involved in synaptic vesicle clustering. The formation of amphisomes following sustained synaptic activity facilitates both the degradation of these proteins and their replenishment through local translation of their mRNAs at presynaptic boutons. We propose that activity-induced synaptic autophagy largely reflects amphisome formation, which in turn is required for the replacement of proteins within the local presynaptic cytomatrix.

neuroscience↗

bioRxiv2021

Autism associated SHANK3 missense point mutations impact conformational fluctuations and protein turnover at synapses

Members of the SH3- and ankyrin-rich repeat (SHANK) protein family are considered as master scaffolds of the post-synaptic density of glutamatergic synapses. Several missense mutations within the canonical SHANK3 isoform have been proposed as causative for the development of autism spectrum disorders (ASDs). However, there is a surprising paucity of data linking missense mutation-induced changes in protein structure and dynamics to the occurrence of ASD-related synaptic phenotypes. In this work, we focus on two ASD-associated point mutations, both located within the same domain of SHANK3. In a proof-of-principle study we demonstrate that both mutant proteins show indeed distinct changes in secondary and tertiary structure as well as higher conformational fluctuations. Local and surprisingly also distal structural disturbances of protein folding result in altered synaptic targeting and changes of protein turnover at synaptic sites.

neuroscience↗

bioRxiv2020

Serum α-Klotho levels correlate with episodic memory changes related to cardiovascular exercise in older adults

Aerobic exercise is a potential life-style intervention to delay cognitive decline and neurodegeneration. Elevated serum levels of the anti-aging protein -Klotho (KL) are a potential mediating factor of exercise benefits on cognition. Here, we examined in older adults how exercise-related changes of KL levels in serum relate to changes in cerebral blood flow (CBF), hippocampal volumes and episodic memory. We analyzed data from a previously published intervention study in which forty cognitively healthy subjects were pseudo-randomly assigned to either a cardiovascular exercise group (treadmill training, n=21) or control group (indoor progressive-muscle relaxation/stretching, n=19). 3-Tesla gadolinium perfusion imaging was used to track hippocampal CBF changes and high resolution 7-Tesla-T1-images were used to track hippocampal volume changes. Changes in episodic memory performance were measured using the complex figure test (CFT). Longitudinal changes were compared between groups and analyzed with a multiple linear regression approach. CFT and hippocampal volume changes significantly predicted changes in serum KL levels. For CFT, this effect was found in the exercise but not the control group. Collectively the data suggest that KL level increases induced by exercise can be associated with improved hippocampal function in older adults.

neuroscience↗

bioRxiv2020

A molecular mechanism by which amyloid-β induces transcriptional inactivation of CREB in Alzheimer's Disease

Synaptic dysfunction caused by soluble {beta}-Amyloid (A{beta}) is a hallmark of the early stage of Alzheimers disease (AD) and is tightly linked to cognitive decline. A{beta} induces by yet unknown mechanisms disruption of transcriptional activity of cAMP- responsive element-binding protein (CREB), a master regulator of cell survival and plasticity-related gene expression. Here, we report that A{beta} elicits cytonuclear trafficking of Jacob, a protein serves as a mobile signaling hub that docks a signalosome to CREB, which induces transcriptional inactivation and subsequent synapse impairment and eventually loss in AD. The small chemical compound Nitarsone selectively hinders assembly of this signalosome and thereby restores CREB transcriptional activity. Nitarsone prevents impairment of synaptic plasticity as well as cognitive decline in mouse models of AD. Collectively, the data suggest that targeting Jacob induced CREB shutoff is a therapeutic avenue against early synaptic dysfunction in AD.

neuroscience↗

bioRxiv2019

TRAF6 controls excitatory spinogenesis and excitation-inhibition balance thought binding neuroplastin

Synaptogenic mechanisms and their relevance to achieve a correct synapse density and activity in mature neurons are poorly understood. Here, we show that the tumor necrosis factor receptor-associated factor 6 (TRAF6) controls early spinogenesis by binding the cell adhesion molecule neuroplastin which is has been related to synapse formation in vivo. TRAF6-neuroplastin co-precipitations from brain samples and co-transfected HEK cells is explained by direct interaction of the proteins based on three-dimensional modelling and biochemical identification of intracellular amino acids of neuroplastin binding the TRAF-C domain of TRAF6 with micromolar affinity. TRAF6 was not only required for normal spinogenesis but also was strictly necessary to restore failed spinogenesis in neuroplastin-deficient neurons. Independently from neuroplastins extracellular adhesive properties or interaction with another known partner i.e. the plasma membrane Ca2+ ATPases, TRAF6 mediated formation of new postsynapses by neuroplastin overexpression in rat hippocampal neurons. Furthermore, TRAF6-controlled spinogenesis was required for the establishment of a correct synapse density as well as proper synaptic activity and intrinsic neuronal activity as demonstrated with intracellular and extracellular electrophysiological recordings. These findings provide a novel mechanism for early synapse formation that shapes connectivity and functioning of hippocampal neurons.

cell biology↗

bioRxiv2019

SIPA1L2 controls trafficking and signaling of TrkB-containing amphisomes at presynaptic terminals

Amphisomes are transient organelles that derive from fusion of autophagosomes with late endosomes. They rapidly transform into degradative autolysosomes, whereas non-degradative roles of the autophagic pathway have been barely described. Here we show that in neurons BDNF/TrkB receptor bearing Rab7 / Light chain 3 (LC3) - positive amphisomes signal at presynaptic boutons during retrograde trafficking to the soma. Local signaling and inward transport essentially require the Rap GTPase-activating (RapGAP) protein SIPA1L2, which directly binds to TrkB and Snapin to connect TrkB-containing amphisomes to dynein. Association with LC3 regulates the RapGAP activity of SIPA1L2 and thereby retrograde trafficking. Following induction of presynaptic plasticity amphisomes dissociate from dynein at boutons, and this enables local signaling and promotes transmitter release. Accordingly, sipa1l2 knockout mice show impaired BDNF-dependent presynaptic plasticity. Collectively, the data suggest that TrkB-signaling endosomes are in fact amphisomes that during retrograde transport have local signaling capacity in the context of presynaptic plasticity.

neuroscience↗

bioRxiv2018

Radial F-actin Organization During Early Neuronal Development

The centrosome is thought to be the major neuronal microtubule-organizing center (MTOC) in early neuronal development, producing microtubules with a radial organization. In addition, albeit in vitro, recent work showed that isolated centrosomes could serve as an actin-organizing center (Farina et al., 2016), raising the possibility that neuronal development may, in addition, require a centrosome-based actin radial organization. Here we report, using super-resolution microscopy and live-cell imaging, F-actin organization around the centrosome with dynamic F-actin aster-like structures with F-actin fibers extending and retracting actively. Photoconversion/photoactivation experiments and molecular manipulations of F-actin stability reveal a robust flux of somatic F-actin towards the cell periphery. Finally, we show that somatic F-actin intermingles with centrosomal PCM-1 satellites. Knockdown of PCM-1 and disruption of centrosomal activity not only affect F-actin dynamics near the centrosome but also in distal growth cones. Collectively the data show a radial F-actin organization during early neuronal development, which might be a cellular mechanism for providing peripheral regions with a fast and continuous source of actin polymers; hence sustaining initial neuronal development.

neuroscience↗