Biology subjects

Airavaara, M.

Publications and source records attributed to Airavaara, M..

5 recordsLinked to original sources

bioRxiv2026

Title: Unilateral loss of tyrosine hydroxylase in adult midbrain dopaminergic neurons reveals reduction to neuregulin1 in rat model of acute dopaminergic dysfunction

Dopamine, produced primarily in the midbrain, is required for movement and reward-based signaling all throughout life. Loss of dopaminergic function can result in changes to motor systems, mood, motivation, and cognition. Dopaminergic cell death or dopaminergic hypofunction are implicated in a variety of diseases including synucleinopathies, neuropsychiatric disorders, and substance use disorders. Loss of dopaminergic neurons (DANs) in the substantia nigra pars compacta (SNpc) and subsequent dysregulation of dopamine signaling in striatum are implicated to varying degrees in all synucleinopathies. By the time patients present with motor symptoms in Parkinson's disease, the most common synucleinopathy, >30% of DANs are lost in the SNpc because of ongoing degeneration for years prior to diagnosis. Studying the early consequences of dopamine loss is critical to understanding mechanisms of dopamine depletion disease progression and identifying biomarkers for earlier diagnosis so that effective treatment can ensue. Here, we created a model of dopamine loss in adult rats to study early transcriptional changes following loss of dopamine synthesis. We used CRISPR to knock out tyrosine hydroxylase (TH), the rate-limiting enzyme for dopamine synthesis, in the adult rat midbrain through injection of Th guide RNAs into transgenic rats expressing Cas9 nuclease specifically in dopamine transporter positive neurons and performed single nucleus RNA sequencing on midbrain and dorsal striatal tissue. Two weeks after injection, we measured a 90% loss of TH and dopamine in the midbrain, but striatal TH and dopamine were unaffected. Despite preceding striatal dopamine loss, our data identified alterations to genes involved in synaptic signaling, organization, and function in both midbrain and striatal neurons. We found the neurotrophic factor, neuregulin1, to be significantly reduced in dopaminergic neurons, which may account for transcriptional changes in surrounding cells that precede detectable reductions to striatal dopamine. These data establish a new rat model of adult TH loss and identify early transcriptional consequences of dopamine loss in the adult midbrain after normal development, providing potential biomarkers for early-stage dopamine loss in PD, synucleinopathies and related disorders of dopamine depletion.

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↗

bioRxiv2022

PKB/AKT attenuates Lewy Body-like pathology in primary neurons via Cathepsins B and D

Motor symptoms of Parkinsons disease (PD) are caused by the loss of dopamine neurons in the substantia nigra pars compacta. Current PD therapies offer only symptomatic relief, and the research on novel ways to stop or slow down the degeneration of dopamine neurons in PD attracts considerable efforts. A characteristic feature of PD is the abnormal accumulation and spread of misfolded -synuclein (-syn) protein leading to the formation of Lewy neurites and bodies in different neuronal populations, including dopamine neurons. The process of Lewy body formation compromises neuronal functions and contributes to the progression of the disease and neurodegeneration in PD patients. Treatments preventing -syn misfolding, aggregation and/or spread may therefore provide much-needed disease-modifying therapies for PD. We and others have demonstrated that -syn aggregation and Lewy body formation can be modelled in primary neuronal cultures treated with -syn pre-formed fibrils (PFFs). Using this approach, we have identified several factors preventing the accumulation of phosphorylated -syn in dopamine neurons in vitro and in vivo. In particular, we and others have demonstrated a prominent role of PKB/AKT pathway activation in promoting the survival of dopamine neurons. Here, we utilize lentiviral vectors (LVs) to express constitutively active myristoylated serine-threonine protein kinase AKT1 (mAKT1) in primary dopamine neurons. We show that lentivirally-delivered mAKT1 promoted survival of dopamine neurons after thapsigargin-induced endoplasmic reticulum (ER) stress and prevented fibril-induced accumulation of phosphorylated -syn. Furthermore, using pharmacological tools, we demonstrate that this activity of mAKT1 is dependent on the functional Cathepsins B and D. These proof-of-principle results demonstrate the critical importance of lysosomal enzymes for processing misfolded -syn and establish a basis for the use of LVs to develop neuroprotective gene therapy strategies for dopamine neurons in PD.

neuroscience↗

bioRxiv2021

Arg1+ microglia are critical for shaping cognition in female mice

Diversity within microglia, the resident brain immune cells, is reported. Whether microglial subsets constitute different subtypes with intrinsic properties and unique functions has not been fully elucidated. Here, we describe a microglial subtype characterized by the expression of the enzyme Arginase-1, i.e. Arg1 +microglia, which is found predominantly in the cholinergic neuron-rich forebrain region during early postnatal development. Arg1+ microglia are frequently observed in close apposition to neurons and exhibit a distinctive molecular signature reflecting a reactive profile. Arg1 deficiency in microglia results in impaired dendritic spine maturation in the hippocampus where cholinergic neurons project, and cognitive behavioural deficiencies in female mice. Our results expand on microglia diversity and provide insights into distinctive spatiotemporal functions exerted by microglial subtypes.

neuroscience↗

bioRxiv2019

GDNF/RET signaling pathway activation eliminates Lewy Body pathology in midbrain dopamine neurons

Neurodegenerative diseases are associated with proteostasis disturbances and accumulation of fibrillar proteins into insoluble aggregates. Progressive age-related degeneration of dopamine neurons is a primary cause of motor dysfunctions in Parkinsons disease (PD) and substantial evidence supports critical involvement of -synuclein (-syn) in the etiology of PD. -syn is a cytosolic protein present in high concentrations in pre-synaptic neuronal terminals and a primary constituent of intracellular protein aggregates known as Lewy Neurites or Lewy Bodies. Progression of Lewy pathology is a characteristic feature in the PD brains caused by the prion-like self-templating properties of misfolded -syn. Modelling Lewy pathology progression with application of exogenously prepared -syn preformed fibrils, we discovered that glial cell line-derived neurotrophic factor (GDNF) prevented formation of -syn aggregates in dopamine neurons in culture and in vivo after viral vector expression of GDNF. These effects were abolished by CRISPR/Cas9-mediated deletion of receptor tyrosine kinase Ret, the major GDNF signaling pathway. Similar to GDNF, expression of mutated constitutively active RET (RET_MEN2B) was able to protect dopamine neurons. GDNF protection against -syn pathology progression was abolished by Src and attenuated by Akt pathway inhibitors. For the first time, we have shown the neurotrophic factor-mediated protection against the misfolded -syn propagation in dopamine neurons, uncovered underlying receptor and intracellular signaling pathways. These results for the first time demonstrate that activation of GDNF/RET signaling can be an effective therapeutic approach to prevent Lewy pathology spread at early stages of PD.\n\n\n\nO_FIG O_LINKSMALLFIG WIDTH=145 HEIGHT=200 SRC=\"FIGDIR/small/752899v1_ufig1.gif\" ALT=\"Figure 1\">\nView larger version (57K):\norg.highwire.dtl.DTLVardef@1f5109dorg.highwire.dtl.DTLVardef@15e4a2org.highwire.dtl.DTLVardef@15571c8org.highwire.dtl.DTLVardef@a10f7d_HPS_FORMAT_FIGEXP M_FIG C_FIG

neuroscience↗