Biology subjects

Ryazanov, S.

Publications and source records attributed to Ryazanov, S..

6 recordsLinked to original sources

bioRxiv2025

The clinical drug candidate anle138b binds predominantly to the central cavity in lipidic Aβ fibrils and modulates fibril formation.

Alzheimers disease is a specific neurodegenerative disorder, distinct from normal aging, with a growing unmet medical need. It is characterized by the accumulation of amyloid plaques in the brain, primarily consisting of amyloid beta (A{beta}) fibrils. Therapeutic antibodies can slow down the disease, but are associated with potential severe side effects, motivating the development of small molecules to halt disease progression. This study investigates the interaction between the clinical drug candidate small molecule anle138b and lipidic A{beta}40 fibrils of type 1 (L1). L1 fibrils were previously shown to closely resemble fibrils from Alzheimers patients18. Using high-resolution structural biology techniques, including cryo-electron microscopy (cryo-EM), nuclear magnetic resonance (NMR) spectroscopy enhanced by dynamic nuclear polarization (DNP), and molecular dynamics (MD) simulations, we find that anle138b selectively binds to a cavity within the fibril. This structural insight provides a deeper understanding of a potential drug-binding mechanism at the atomic level and may inform the development of novel therapies and diagnostic approaches. In addition, anle138b reduces fibril formation in the presence of lipids by approximately 75%. This may suggest a mechanistic connection to its previously reported activity in animal models of Alzheimers disease15.

biochemistry↗

bioRxiv2025

Structural insight into binding of novel PET tracer MODAG-005 to lipidic ????-Synuclein fibrils

Accumulation of -synuclein (Syn) aggregates in the human brain is the major hallmark of synucleinopathies such as Parkinsons Disease, Multiple System Atrophy, and Dementia with Lewy bodies. Positron Emission Tomography (PET) plays a vital role in diagnosing these diseases and monitoring their progression by enabling the non-invasive and sensitive detection of Syn aggregates in the brain. However, developing PET tracers with specific target binding, as well as identifying the binding site and complex structure present significant challenges. Here, we investigated the interaction between lipidic Syn aggregates and MODAG-005, a new Syn PET tracer candidate, using nuclear magnetic resonance spectroscopy, cryogenic electron microscopy and molecular dynamics (MD) simulations. Two binding sites of MODAG-005 were found, one on the surface and one in a tubular cavity of the fibril, of which the occupancies were found to depend on the preparation protocols. The cavity binding site is thermodynamically more stable than the external binding site and is the only site occupied when MODAG-005 is applied with liposome as carriers to the aggregates. This is corroborated by MD simulations in which stable interactions between MODAG-005 and glycine containing backbone motifs of the tubular cavity of the aggregates are observed.

biochemistry↗

bioRxiv2025

Anle138b ameliorates pathological phenotypes in mouse and cellular models of Huntington's disease

Huntingtons disease (HD) is a debilitating hereditary movement disorder caused by a CAG repeat expansion in the huntingtin gene. HD is characterized by deposition of mutant huntingtin (mHTT) aggregates, and by severe neurodegeneration of the basal ganglia and neocortex. No cure is currently available, and new treatment options are urgently needed. Here, we show that the oligomer modifying molecule anle138b (INN: emrusolmin) improves multiple disease phenotypes in cell culture and in two mouse models of HD. Application of anle138b reduced mHTT aggregate formation and ameliorated neurotoxicity in primary neurons. Oral administration of anle138b delayed deposition of mHTT inclusions, reduced brain atrophy, mitigated neuroinflammation, improved motor function and extended life span in HD mice. Downregulation of striatal markers and synapse loss in striatal spiny projection neurons were also partially rescued. No adverse effects of anle138b were observed in wildtype animals. Moreover, anle138b markedly decreased mHTT aggregation in human neural precursor cells differentiated from HD patient-derived induced pluripotent stem cells (iPSCs). Altogether these results illustrate the potential of anle138b as a disease-modifying treatment for HD.

neuroscience↗

bioRxiv2024

The amyloid oligomer modulator anle138b has disease modifying effects in a human IAPP transgenic mouse model of type 2 diabetes mellitus (hIAPP Ob/Ob mice)

Aims/HypothesisType 2 diabetes mellitus (T2DM) is a common metabolic disease, characterized by impaired insulin action, often called "insulin resistance", in conjunction with a decline in insulin secretion by the pancreatic islet beta cells, referred to as "beta cell failure". Both conditions contribute to causing hyperglycemia, which is the central feature of T2DM. Cytotoxic aggregates of the beta cell hormone human islet amyloid polypeptide (hIAPP), promote T2DM pathogenesis by damaging the pancreatic islet beta cells and reducing insulin secretion. Anle138b is an amyloid oligomer modulator with demonstrated disease-modifying properties in mouse models of neurodegenerative diseases linked to protein aggregation, and is currently in a phase 2 clinical trial. We therefore tested whether anle138b can reduce hyperglycemia in a severe hIAPP transgenic mouse model of T2DM. MethodsAnle138b was administered orally via dietary admixture to male hIAPP Ob/Ob mice and Ob/Ob controls; blood glucose-, insulin-, and glycated hemoglobin (HbA1c) levels were measured at different timepoints over 34 weeks; in addition, the effects of anle138b on the histomorphology of the pancreatic islets was determined. Finally, anle138b effects on mitochondrial toxicity of hIAPP aggregates was assessed in vitro. ResultsOral administration of anle138b in male hIAPP Ob/Ob mice potently reduced hyperglycemia and glycated HbA1c levels compared to non-treated mice (at 34 weeks, mean glucose level non-treated: 30 {+/-} 1.3 mM, treated: 15 {+/-} 2.2 mM (p < 0.001); at 32 weeks, mean HbA1c level non-treated: 77 {+/-} 3.3 mM/M, treated: 41 {+/-} 5.3 mM/M (p < 0.01)), in a hIAPP-dependent way. In addition, anle138b increased both the number of pancreatic islets as well as the overall islet beta cell mass (by 54% and 58%, respectively) in hIAPP Ob/Ob mice. In vitro, anle138b inhibited toxic effects of hIAPP on mitochondria, such as mitochondrial swelling (decreased by 92%, p < 0.01), release of cytochrome c (decreased by 63.7%, p < 0.001) and lowered mitochondrial membrane potential (increased by 62%, p < 0.001). Conclusions/InterpretationCollectively, our results indicate that anle138b is a promising clinical drug candidate for preserving islet function and reducing hyperglycemia in T2DM, in part by mitigating mitochondrial dysfunction. Research in ContextO_ST_ABSWhat is already known about this subject?C_ST_ABSO_LIType 2 diabetes mellitus (T2DM) is characterized by hyperglycemia, which stems from impaired insulin action coupled with declining insulin secretion from pancreatic islet beta cells. C_LIO_LIAggregation of the beta cell hormone human islet amyloid polypeptide (hIAPP) plays a crucial role in the loss and dysfunction of the insulin-secreting beta cells. C_LIO_LIThe small-molecule anle138b effectively modulates the aggregation of amyloidogenic proteins in neurodegenerative conditions such as Alzheimers and Parkinsons disease. C_LI What is the key question?O_LICan the oligomer modulator anle138b ameliorate the diabetic phenotype in a severe hIAPP transgenic mouse model of T2DM (hIAPP Ob/Ob) ? C_LIO_LIWhat are the new findings? C_LIO_LIOral treatment of hIAPP Ob/Ob mice with anle138b causes reduced hyperglycemia and reduced glycated hemoglobin (HbA1c) levels, in a hIAPP-dependent manner. C_LIO_LIAnle138b increases pancreatic islet number and beta cell mass and restores the inverse relation between insulin and glucose in hIAPP Ob/Ob mice. C_LIO_LIIn vitro anle138b inhibits toxic effects of hIAPP aggregates on mitochondria. C_LI How might this impact on clinical practice in the foreseeable future?O_LIAnle138b could be introduced as a promising clinical drug candidate for slowing down disease progression of T2DM. C_LI

pathology↗

bioRxiv2020

Effects of pharmacological modulators of α-synuclein and tau aggregation and internalization

Parkinsons disease (PD) and Alzheimers disease (AD) are common neurodegenerative disorders of the elderly and, therefore, affect a growing number of patients worldwide. Both diseases share, as a common hallmark, the accumulation of characteristic protein aggregates, known as Lewy bodies (LB) in PD, and neurofibrillary tangles in AD. LBs are primarily composed of misfolded -synuclein (aSyn), and neurofibrillary tangles are primarily composed of tau protein. Importantly, upon pathological evaluation, most AD and PD/Lewy body dementia cases exhibit mixed pathology, with the co-occurrence of both Lewy bodies and neurofibrillary tangles, among other protein inclusions. Recent studies suggest that both aSyn and tau pathology can spread and propagate through neuronal connections. Therefore, it is important to investigate the mechanisms underlying aggregation and propagation of these proteins for the development of novel therapeutic strategies. Here, we assessed the effects of different pharmacological interventions on the aggregation and internalization of tau and aSyn. We found that anle138b and epigallocatechin gallate decrease aSyn aggregation, that fulvic acid attenuates aggregation of the repeat domain of tau, and that dynasore reduces tau internalization. Establishing the effects of small molecules with different chemical properties on the aggregation and spreading of aSyn and tau will be important for the development of future therapeutic interventions.

neuroscience↗

bioRxiv2018

Depopulation of α-synuclein aggregates is associated with rescue of dopamine neuron dysfunction and death in a new Parkinson disease model

Parkinsons Disease (PD) is characterized by the presence of -synuclein aggregates known as Lewy bodies and Lewy neurites, whose formation is linked to disease development. The causal relation between -synuclein aggregates and PD is not well understood. We generated a new transgenic mouse line (MI2) expressing human, aggregation-prone truncated 1-120 -synuclein under the control of the tyrosine hydroxylase promoter. MI2 mice exhibit progressive aggregation of -synuclein in dopaminergic neurons of the substantia nigra pars compacta and their striatal terminals. This is associated with a progressive reduction of striatal dopamine release, reduced striatal innervation and significant nigral dopaminergic nerve cell death starting from 6 and 12 months of age, respectively. Overt impairment in motor behavior was found in MI2 mice at 20 months of age, when 50% of dopaminergic neurons are lost. These changes were associated with an increase in the number and density of 20-500nm -synuclein species as shown by dSTORM. Treatment with the oligomer modulator anle138b, from 9-12 months of age, restored striatal dopamine release and prevented dopaminergic cell death. These effects were associated with a reduction of the inner density of -synuclein aggregates and an increase in dispersed small -synuclein species as revealed by dSTORM. The MI2 mouse model recapitulates the progressive dopaminergic deficit observed in PD, showing that early synaptic dysfunction precedes dopaminergic axonal loss and neuronal death that become associated with a motor deficit upon reaching a certain threshold. Our data also provide new mechanistic insight for the effect of anle138bs function in vivo supporting that targeting -synuclein aggregation is a promising therapeutic approach for PD.

neuroscience↗