Mart Saarma

Major vulnerability factors for psychiatric disorders such as depression, that often prevent complete remission and lead to relapses, are temperamental. In a rat model of clustered persistent high-anxiety/low-motivation, we have found that overexpression of glial cell line-derived neurotrophic factor (GDNF) by intra-striatally administered adeno-associated virus vector completely converts the passive coping style of low exploratory rats into an active one, similar to high exploratory rats. This conversion of the behavioural strategy developed gradually over repeated testing, and was associated with increased catecholamine metabolism in several brain regions and changes in the regulation of serotonin neurotransmission. An increase in dopamine transporter availability in the striatum was necessary for the phenotype conversion. Associated changes in striatal gene expression included key regulators of monoamine storage and epitranscriptomic regulation. The increase in GDNF signalling also caused alterations in levels and regional covariation of oxidative metabolism, suggestive of a reorganization of neural activity throughout the brain. Thus, neurotrophic factors, GDNF in particular, may play a pivotal role in the development, persistence and alteration of temperament/personality traits, and therefore constitute a potential target for treatment of chronic, relapsing psychiatric disorders.

The concept of scientific wealth is defined as the average number of citations per paper published by scientists from a given country or territory over a fixed period. This analysis is based on data from Essential Science Indicators (ESI; Clarivate^TM), which ranks authors, institutions, countries, and journals according to publication and citation performance between 2014 and 2024. Twenty years ago, Estonia’s scientific impact was 20% below the ESI world average. Today, the average citation rate of articles by Estonian researchers is 81.7% above the ESI world average, placing Estonia third globally, after Iceland and Singapore, and ahead of its Nordic neighbors and role models, Finland and Sweden. The rapid growth of Estonian science has yet to be fully explained. None of the four groups of factors analyzed ‒ science policies, funding, foreign aid, and research ethos ‒ can fully explain Estonia’s success on its own, especially when compared to its Baltic neighbors, Latvia and Lithuania. Estonia is a prime example of how a fortunate combination of factors can lead to the fastest growth in scientific wealth worldwide, although this specific combination remains to be identified.

Cerebral dopamine neurotrophic factor (CDNF) was identified for ability to rescue midbrain dopamine neurons and as endoplasmic reticulum (ER)-located protein that can be secreted. Structurally homologous to mesencephalic astrocyte-derived neurotrophic factor (MANF), CDNF has been shown to interact with ER-localized chaperone BiP. The ER plays a crucial role in protein synthesis, folding, and quality control, with BiP being a key player in maintaining protein homeostasis. CDNF is protective against ER stress and involved in regulating the unfolded protein response (UPR) signaling and interaction with BiP. Recent studies have shown that CDNF interacts with UPR sensor proteins PERK, IRE1α, and ATF6, suggesting an overlap in CDNF binding with UPR sensors and BiP. In rodent models of Parkinson’s disease (PD), CDNF protects and restores the function of brain dopamine neurons and was successful in PD phase 1 clinical studies. CDNF has shown therapeutic potential for several neurological diseases, including amyotrophic lateral sclerosis, and ischemic stroke. Despite extensive knowledge on CDNF’s impact on cellular function and neuronal degeneration, its detailed molecular mechanism of action in the ER remains unclear. Here, we have characterized the CDNF interaction with BiP both structurally and functionally and solved the crystal structures of CDNF-BiP complexes to 1.5 Å resolution, complemented with molecular dynamics simulations. Results show CDNF’s role as an antagonist of BiP nucleotide exchange, and thus in its chaperone function, binding to the ADP-bound state. Finally, we show its effect on neuroprotection with stem cell-derived human dopamine neurons, highlighting its potential in neurodegenerative disease treatment.

The receptor tyrosine kinase RET (rearranged during transfection) is critical for many physiological processes, particularly in the development and function of the nervous system, male reproductive system and renal system. RET signaling is activated physiologically by glial cell line-derived neurotrophic factor family (GDNF) ligands or growth differentiation factor 15 (GDF15) via GDNF family receptor α (GFRα) or GDNF family receptor α-like (GFRAL) co-receptors, respectively, regulating a variety of cellular responses including cell survival, migration, differentiation, proliferation and metabolism. RET is essential for neuronal development, maintenance and axon guidance in the nervous system. RET signaling is critical for kidney and spermatogonia development and the enteric nervous system development and maintenance. Inactivating mutations in the receptor are the primary cause of Hirschsprung disease, a rare intestinal motility disorder characterized by aganglionic megacolon. This review covers the molecular mechanism of RET signaling, its role in the early stages of the nervous system and kidney development during early embryogenesis, and different diseases. It highlights the importance of RET receptors as therapeutic targets.

Major vulnerability factors for psychiatric disorders such as depression, that often prevent complete remission and lead to relapses, are temperamental. In a rat model of clustered persistent high anxiety/low motivation, we have found that overexpression of glial-cell-line-derived neurotrophic factor (GDNF) by intra-striatally administered adeno-associated virus vector strikingly converts the passive coping style of low exploratory rats into an active one, similar to high exploratory rats. This conversion of behavioural strategy developed gradually over repeated testing, and was associated with increased catecholamine metabolism in several brain regions and changes in the regulation of serotonin neurotransmission. An increase in in vivo dopamine transporter availability in the striatum was necessary for the phenotype conversion. Associated changes in striatal gene expression included key players in monoamine storage and epitranscriptomic regulation. The increase in GDNF signalling also caused alterations in levels and regional covariation of oxidative metabolism, indicative of persistent reorganization of neural activity throughout the brain. Thus, neurotrophic factors, GDNF in particular, may play a pivotal role in the development, persistence and alteration of personality traits, and therefore constitute a potential target for treatment of chronic, relapsing psychiatric disorders.

SUMMARY: Cerebral dopamine neurotrophic factor (CDNF) is an unconventional trophic factor that protects dopamine neurons in cellular and animal models of Parkinson’s disease (PD). CDNF was safe and well tolerated in phase 1 clinical trials for PD treatment, and currently, its peptide analogue is under investigation in phase 1 clinical trials for PD. Despite prominent neuroprotective and neurorestorative activity, the receptors and exact mechanism of CDNF functioning have been obscure. Intracellularly acting CDNF exerts cytoprotection by attenuating endoplasmic reticulum (ER) stress and unfolded protein response (UPR). We demonstrated that this activity occurs through the direct binding of CDNF to ER transmembrane UPR sensors PERK and IRE1α for purified proteins and in cells. We identified CDNF mutants deficient for binding to UPR sensors. CDNF binding to PERK and IRE1α appeared to be crucial for the survival of mouse dopamine neurons in culture. Importantly for clinical translation, CDNF rescues human induced pluripotent stem cell-derived dopamine neurons and promotes their regeneration. CDNF binding to UPR sensors alleviated terminal UPR and promoted neurite outgrowth of human dopamine neurons through direct binding to PERK and IRE1α. CDNF binding to BiP was dispensable for the neuroprotective and neurorestorative activity of CDNF. Therefore, CDNF, or small molecules mimicking its binding to UPR sensors and acting selectively on dopamine neurons with activated UPR, are promising drug candidates for PD treatment.

Brain diseases are the most devastating problem among the world’s increasingly aging population, and the number of patients with neurological diseases is expected to increase in the future. Although methods for delivering drugs to the brain have advanced significantly, none of these approaches provide satisfactory results for the treatment of brain diseases. This remains a challenge due to the unique anatomy and physiology of the brain, including tight regulation and limited access of substances across the blood-brain barrier. Nanoparticles are considered an ideal drug delivery system to hard-to-reach organs such as the brain. The development of new drugs and new nanomaterial-based brain treatments has opened various opportunities for scientists to develop brain-specific delivery systems that could improve treatment outcomes for patients with brain disorders such as Alzheimer’s disease, Parkinson’s disease, stroke and brain tumors. In this review, we discuss noteworthy literature that examines recent developments in brain-targeted nanomedicines used in the treatment of neurological diseases.

Obesity, a global health challenge, is a major risk factor for multiple life-threatening diseases, including diabetes, fatty liver, and cancer. There is an ongoing need to identify safe and tolerable therapeutics for obesity management. Herein, we show that treatment with artesunate, an artemisinin derivative approved by the FDA for the treatment of severe malaria, effectively reduces body weight and improves metabolic profiles in preclinical models of obesity, including male mice with overnutrition-induced obesity and male cynomolgus macaques with spontaneous obesity, without inducing nausea and malaise. Artesunate promotes weight loss and reduces food intake in obese mice and cynomolgus macaques by increasing circulating levels of Growth Differentiation Factor 15 (GDF15), an appetite-regulating hormone with a brainstem-restricted receptor, the GDNF family receptor α-like (GFRAL). Mechanistically, artesunate induces the expression of GDF15 in multiple organs, especially the liver, in mice through a C/EBP homologous protein (CHOP)-directed integrated stress response. Inhibition of GDF15/GFRAL signalling by genetic ablation of GFRAL or tissue-specific knockdown of GDF15 abrogates the anti-obesity effect of artesunate in mice with diet-induced obesity, suggesting that artesunate controls bodyweight and appetite in a GDF15/GFRAL signalling-dependent manner. These data highlight the therapeutic benefits of artesunate in the treatment of obesity and related comorbidities.

Modification of mRNA by methylation is involved in post-transcriptional regulation of gene expression by affecting the splicing, transport, stability and translation of mRNA. Methylation of adenosine at N ⁶ (m ⁶ A) is the most common and most important cellular modification occurring in the mRNA of eukaryotes. Evidence that m ⁶ A mRNA methylation is involved in regulation of stress response and that its dysregulation may contribute to the pathogenesis of neuropsychiatric disorders is accumulating. We have examined the acute and subchronic (up to 18 days once per day intraperitoneally) effect of the first METTL3/METTL14 activator compound CHMA1004 (methyl-piperazine-2-carboxylate) at two doses (1 and 5 mg/kg) in male and female rats. CHMA1004 had a profound locomotor activating and anxiolytic-like profile in open field and elevated zero-maze tests. In female rats sucrose consumption and swimming in Porsolt’s test were increased. Nevertheless, CHMA1004 did not exhibit strong psychostimulant-like properties: CHMA1004 had no effect on 50-kHz ultrasonic vocalizations except that it reduced the baseline difference between male and female animals, and acute drug treatment had no effect on extracellular dopamine levels in striatum. Subchronic CHMA1004 altered ex vivo catecholamine levels in several brain regions. RNA sequencing of female rat striata after subchronic CHMA1004 treatment revealed changes in the expression of a number of genes linked to dopamine neuron viability, neurodegeneration, depression, anxiety and stress response. Conclusively, the first-in-class METTL3/METTL14 activator compound CHMA1004 increased locomotor activity and elicited anxiolytic-like effects after systemic administration, demonstrating tha pharmacological activation of RNA m ⁶ A methylation has potential for neuropsychiatric drug development.