α-synuclein (αSN) protein was first isolated in 1988 from the electric organ of the electric ray species Torpedo californica. The name “synuclein” was proposed based on its localization in the presynaptic nerve terminals (“syn” from synaptic), and proximity to the nuclear envelope of neurons (“nuclein” from nucleic). αSN is heavily investigated due to its propensity to aggregate. Its ability to form amyloid fibrils and oligomers have been linked to its toxicity from many years. The intracellular inclusions called Lewy bodies (LBs) and Lewy neurites (LNs) are the neuropathological hallmark of Parkinson’s disease (PD). LBs are mainly composed of αSN, which suggests its central role in this disorder. Indeed, mutation in the αSN gene, or its multiplication, enhance the development of β-sheet-rich structures and are responsible for the early onset familial form of PD. αSN pathology and formation of LBs have been also reported in many other neurodegenerative disorders, which are nowadays classified as synucleinopathies. Most notably is the second most common form of dementia, Dementia with Lewy bodies (DLB) and multiple system atrophy (MSA).
Despite intensive studies the true role of αSN in the cells remains unknown. In neurons, it has been proposed to facilitate the exocytosis, regulates synaptic vesicles trafficking or takes part in neurite outgrowth and adhesion of brain cells. Under physiological conditions, a part of its presynaptic localization, αSN is also readily released into extracellular space. However, the function of extracellular αSN is still not known. In our in vitro model, using primary neuronal cultures, we are investigating the role of extracellular αSN in regulation of presynaptic activity, SV recycling and glutamate release.
α-synuclein – aggregation and its monitoring
We are investigating molecules and conditions that enhance αSN aggregation and try to find a way to stop that phenomenon. Moreover, we are engaged in the screenings for potential PET tracers able to specifically detect αSN deposits in the brain. Furthermore, in our research, we use αSN based animal models of PD, where we try to find ways to reduce its fibrillation and toxicity in the central nervous system.
α-synuclein – interactions and spreading
In our studies we focus on both αSN aggregation propensity, but also try to find compounds/protein interacting with αSN and discover its exact role in the nerve cells. Recently we found that αSN is present on lipoprotein vesicles in the human cerebrospinal fluid (CSF). This interaction rather depends on the αSN propensity to bind to the negatively charged lipid particles and approximately 45% of CSF αSN is bound to ApoE-positive lipoproteins. Along with the presence of ApoE in some dopaminergic neurons and the cellular uptake of αSN-enriched lipoproteins, this observation represents a possible mechanism for αSN uptake and spreading in the brain.
Researchers: Wojciech Paslawski, Vesna Lazarevic, Justyna Zareba Paslawska, Xiaoqun Zhang,
α-synuclein-lipoprotein interactions and elevated ApoE level in cerebrospinal fluid from Parkinson’s disease patients. Paslawski W, Zareba-Paslawska J, Zhang X, Hölzl K, Wadensten H, Shariatgorji M, Janelidze S, Hansson O, Forsgren L, Andrén PE, Svenningsson P. Proc Natl Acad Sci U S A. 2019 Jul 23;116(30):15226-15235. doi: 10.1073/pnas.1821409116.
Depressive-like phenotype induced by AAV-mediated overexpression of human α-synuclein in midbrain dopaminergic neurons. Caudal D, Alvarsson A, Björklund A, Svenningsson P. Exp Neurol. 2015 Nov;273:243-52. doi:10.1016/j.expneurol.2015.09.002
Emotional memory impairments induced by AAV-mediated overexpression of human α-synuclein in dopaminergic neurons of the ventral tegmental area. Alvarsson A, Caudal D, Björklund A, Svenningsson P. Behav Brain Res. 2016 Jan 1;296:129-133. doi: 10.1016/j.bbr.2015.08.034.
The tau proteins are a group of six isoforms produced by alternative splicing for the MAPT gene. Tau proteins are highly enriched in the brain and primarily involved in maintaining stability of neuronal axons. Four repeat tau isoforms form aggregates in astrocytes and is patognomonic in the atypical parkinson diseases, progressive supranuclear palsy (PSP) and corticobasal degeneration (CBD). Our work aim at intervene with the spreading of tau in the brain.
Researchers: Justyna Zareba-Paslawska.
Tau Isoform-Driven CBD Pathology Transmission in Oligodendrocytes in Humanized Tau Mice. Zareba-Paslawska J, Patra K, Kluzer L, Revesz T, Svenningsson P. Front Neurol. 2021 Jan 15;11:589471. doi: 10.3389/fneur.2020.589471.
Mutations in the glucocerebrosidase (GBA) gene, encoding the lysosomal protein glucocerebrosidase (GCase), is the strongest genetic risk factor for PD. Heterozygote or homozygote (i.e. Gaucher disease (GD) patients) carriers of GBA mutations have 10-15-fold increased risk to develop synucleopathies including PD. The activity of GCase is counteracted by these mutations, but this enzyme can also be inhibited by α-synuclein.
Prosaposin (PSAP) is a neurotrophic and neuroprotective factor which can be found in brain tissue and various body fluids. In addition to its neuroprotective role, PSAP serves as a precursor of saposins A-D, which are essential activators for several lysosomal hydrolases. PSAP is cleaved in the late endosomes/lysosomes and gives rise to four saposins. Among four saposins, saposin C, which is required for a normal function of GCase, has been suggested as a disease modifier of PD. Some studies also argue that neuroprotective effects of PSAP and saposin C are mediated by orphan G-protein coupled receptors GPR37 and GPR37L1.
Our aim is to investigate the molecular mechanisms underlying the neuroprotective role of PSAP/saposin C using both in vitro cellular models and in vivo mouse models.
Researchers: Yachao He, Rika Kojima, Xiaoqun Zhang,
GBA RNAi but not catalytic inhibition of glucocerebrosidase with Conduritol-β-epoxide increases levels of total α-synuclein in SH-SY5Y cells. Zurbruegg M, Chan MY, Svenningsson P. Neurosci Lett. 2019 Jul 27;706:217-222. doi: 10.1016/j.neulet.2019.05.027.
GPR37 protein trafficking to the plasma membrane regulated by prosaposin and GM1 gangliosides promotes cell viability. Lundius EG, Vukojevic V, Hertz E, Stroth N, Cederlund A, Hiraiwa M, Terenius L, Svenningsson P. J Biol Chem. 2014 Feb 21;289(8):4660-73. doi: 10.1074/jbc.M113.510883. Epub 2013 Dec 26