Biology subjects

Lindholm, P.

Publications and source records attributed to Lindholm, P..

6 recordsLinked to original sources

bioRxiv2025

Experimental change in personality: Overexpression of GDNF in the rat striatum converts the low exploratory phenotype into highly explorative

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.

neuroscience↗

bioRxiv2025

Non-invasive peripheral delivery of CDNF fragment protects neurons in models of Parkinsons and ALS

Non-invasive delivery of brain therapeutics is a key challenge for treating neurodegenerative diseases. Here, we discovered a novel carboxy (C)-terminal fragment of cerebral dopamine neurotrophic factor (C-CDNF) that protects dopamine (DA) and motoneurons (MNs) in rodent models of Parkinsons disease (PD) and amyotrophic lateral sclerosis (ALS). C-CDNF retains the same structure as CDNF and similarly to CDNF regulates cell stress pathways but unorthodoxly enters cultured neurons and passes through the blood-brain barrier. In vivo, intracranially or peripherally delivered C-CDNF improves motor deficits, protects DA neurons, and restores motor behavior in a rat model of PD. Subcutaneous C-CDNF also protects MNs and reduces microglial activation in an ALS model. Based on our findings, beginning C-CDNF treatment soon after diagnosis is anticipated to delay progression of PD and ALS, thereby improving treatment outcome. Thus, systemic delivery of C-CDNF should simplify the administration of protein-based therapeutics to patients while reducing treatment risk and financial burden for patients and families.

neuroscience↗

bioRxiv2023

A novel method for tracking nitrogen kinetics in vivo and ex vivo using radioactive nitrogen-13 gas and Positron Emission Tomography

RationaleDecompression sickness (DCS) is caused by gaseous nitrogen dissolved in tissues forming bubbles during decompression. To date no method exists to identify nitrogen within tissues, but with advances in PET technology it may be possible to track gaseous radionuclides into tissues. We aimed to develop a method to track nitrogen movement in vivo that could then be used to further our understanding of DCS using nitrogen-13 (13N2) - a radioactive isotope of nitrogen that emits {beta}+ radiation. MethodsA single anesthetized and ventilated Sprague Dawley rat lay supine inside a PET scanner for 30 min. The rat breathed oxygen for the first 2 min, then was switched to a bag containing 13N2 gas mixed with oxygen for 20 min, then breathed oxygen alone for the final 8 min. Gas samples were drawn from the inspiratory line at 5, 15 and 25 min. The PET scanner recorded 13N2 with energy windows of 250-750 keV. Following the scan, a mixed blood sample was taken from the heart, while the brain, liver, femur and thigh muscle were removed to determine organ radioactivity using a gamma counter. ResultsThe gas samples at 5 (5.7 kbq.ml-1) and 15 min (5.3 kbq.ml-1) showed radioactivity in the inspired gas that was absent at 25 min (0.1 kbq.ml-1), when the 13N2 was stopped. The signal intensity in the PET scanner increased from baseline (0.03) to 2-12 min (0.68{+/-}0.31), and 12-22 min (0.88{+/-}0.06), before reducing slightly from 22-30 min (0.61{+/-}0.04). All organs had radioactivity when measured in the gamma counter, with the highest counts in the liver (12593 counts.min-1.g-1) and the lowest in the muscle (2687 counts.min-1.g-1). Principal ConclusionsThis study successfully demonstrated a quantitative 3D imaging method of tracking nitrogen gas through the body both in vivo and ex vivo using PET.

physiology↗

bioRxiv2022

Ageing disrupts MANF-mediated immune modulation during skeletal muscle regeneration

Age-related decline in skeletal muscle regenerative capacity is multifactorial, yet, the contribution of immune dysfunction to regenerative failure is unknown. Here, we uncover a new mechanism of immune modulation operating during skeletal muscle regeneration that is disrupted in aged animals and relies on the regulation of macrophage function. The immune modulator MANF is induced following muscle injury in young mice, but not in aged animals, and its expression is essential for regenerative success. Regenerative impairments in the aged muscle are associated with defects in the repair-associated myeloid response similar to those found in MANF-deficient models and could be improved through MANF delivery. We propose that restoring the myeloid response through immune modulation is a promising therapeutic strategy to improve the regenerative capacity of aged muscles.

cell biology↗

bioRxiv2020

MANF regulates unfolded protein response and neuronal survival through its ER-located receptor IRE1α

Mesencephalic astrocyte-derived neurotrophic factor (MANF) is an endoplasmic reticulum (ER)-located protein with cytoprotective effects in numerous cell types in vitro and in models of neurodegeneration and diabetes in vivo. So far, the exact mode of its action has remained elusive and plasma membrane or ER-located receptors of MANF have not been identified. We have found that MANF can directly interact with transmembrane unfolded protein response (UPR) receptor IRE1 and compete with the major ER chaperone BiP (GRP78) for the interaction with IRE1. With lower affinities MANF can also interact with other UPR receptors, PERK and ATF6. Using molecular modeling and mutagenesis analysis, we have identified the exact structural MANF regions involved in its binding to the luminal domain of IRE1. MANF attenuates UPR signaling by decreasing IRE1 oligomerization and IRE1 phosphorylation. MANF mutant deficient in IRE1 binding cannot regulate IRE1 oligomerization and fails to protect neurons from ER stress induced death. Importantly, we found that MANF-IRE1 interaction is also crucial for the survival promoting action of MANF for dopamine neurons in an animal model of Parkinsons disease. Our data reveal a novel mechanism of IRE1 regulation during ER stress and demonstrate the intracellular mode of action of MANF as a modulator of UPR and neuronal cell survival through the direct interaction with IRE1 and regulation of its activity. Furthermore, our data explain why MANF in contrast to other growth factors has no effects on naive cells and rescues only ER stressed or injured cells.

cell biology↗

bioRxiv2020

CDNF rescues motor neurons in three animal models of ALS by targeting ER stress

The role of chronic endoplasmic reticulum (ER) stress in the pathophysiology of Amyotrophic lateral sclerosis (ALS), as well as a potential drug target, has received increasing attention. Here, we investigated the mode of action and therapeutic effect of the ER resident protein cerebral dopamine neurotrophic factor (CDNF) in preclinical models of ALS harboring different genetic mutations. We identify that intracerebroventricular (i.c.v.) administration of CDNF significantly halts the progression of the disease and improves motor behavior in TDP43-M337V and SOD1-G93A rodent models of ALS. CDNF rescues motor neurons (MNs) in vitro and in vivo from ER stress associated cell death and its beneficial effect is independent of genetic disease etiology. Notably, CDNF regulates the unfolded protein response (UPR) initiated by transducers IRE1, PERK, and ATF6, thereby enhancing MN survival. Thus, CDNF holds great promise for the design of new rational treatments for ALS.

neuroscience↗