Parkinson's disease / alpha-synuclein

Members of the group

Joakim Bergström, PhD, Associate Professor
Martin Ingelsson, MD, Professor
Sara Ekmark-Lewén, PhD
Agata Aniszewska, PhD

Alpha-synuclein pathogenesis - novel targets for development of immunobased therapies in Parkinson’s disease

The protein α-synuclein deposits as Lewy bodies and Lewy neurites inside the neurons of patients with Parkinson’s disease and Lewy body dementia. Large soluble oligomeric or protofibrillar forms of α-synuclein are believed to be particularly neurotoxic for the affected brain.

By working with recombinant forms of α-synuclein oligomers / protofibrils, we are analyzing the formation and effects of such species in vitro and on cell models.

In particular, we are investigating how these species can spread from cell to cell and thereby cause the disease to propagate inside the brain. Moreover, we want to find out how these α-synuclein species can perturb neuronal functions such as neurotransmitter release. We have purified toxic α-synuclein oligomers and used these as antigen to generate monoclonal antibodies. A number of highly selective antibodies have been developed and several of these have been evaluated for immunotherapy on cell and animal models for the actual diseases.

Importantly, we have found that intraperitoneal injections with one of the antibodies can lower the levels of α-synuclein oligomers/protofibrils in transgenic mice and also prolong survival in the same animals. In a current study we are evaluating if the antibody treatment can alleviate the early motor and behavioural symptoms that we recently have demonstrated in this mouse model. Moreover, we seek to adopt the antibodies in assays, such as ELISA; to be able to measure the presence of toxic oligomers / protofibrils as a novel disease biomarker for the actual disorders.

Selected publications

Gustafsson G, Loov C, Persson E, Lazaro DF, Takeda S, Bergstrom J, Erlandsson A, Sehlin D, Balaj L, Gyorgy B, Hallbeck M, Outeiro TF, Breakefield XO, Hyman BT and Ingelsson M (2018). Secretion and Uptake of alpha-Synuclein Via Extracellular Vesicles in Cultured Cells. Cell Mol Neurobiol. 38: 1539-1550.

Almandoz-Gil L, Ingelsson M and Bergstrom J (2018). Generation and Characterization of Stable alpha-Synuclein Oligomers. Methods Mol Biol. 1779: 61-71.

Almandoz-Gil L, Persson E, Lindstrom V, Ingelsson M, Erlandsson A and Bergstrom J (2018). In Situ Proximity Ligation Assay Reveals Co-Localization of Alpha-Synuclein and SNARE Proteins in Murine Primary Neurons. Front Neurol. 9: 180.

Ekmark-Lewen S, Lindstrom V, Gumucio A, Ihse E, Behere A, Kahle PJ, Nordstrom E, Eriksson M, Erlandsson A, Bergstrom J and Ingelsson M (2018). Early fine motor impairment and behavioral dysfunction in (Thy-1)-h[A30P] alpha-synuclein mice. Brain Behav. 8: e00915.

Loov C, Scherzer CR, Hyman BT, Breakefield XO and Ingelsson M (2016). alpha-Synuclein in Extracellular Vesicles: Functional Implications and Diagnostic Opportunities. Cell Mol Neurobiol. 36: 437-48.

Gustafsson G, Eriksson F, Moller C, da Fonseca TL, Outeiro TF, Lannfelt L, Bergstrom J and Ingelsson M (2017). Cellular Uptake of alpha-Synuclein Oligomer-Selective Antibodies is Enhanced by the Extracellular Presence of alpha-Synuclein and Mediated via Fcgamma Receptors. Cell Mol Neurobiol. 37: 121-131.

Cai Y, Lendel C, Osterlund L, Kasrayan A, Lannfelt L, Ingelsson M, Nikolajeff F, Karlsson M and Bergstrom J (2015). Changes in secondary structure of alpha-synuclein during oligomerization induced by reactive aldehydes. Biochem Biophys Res Commun. 464: 336-41.

Lindstrom V, Fagerqvist T, Nordstrom E, Eriksson F, Lord A, Tucker S, Andersson J, Johannesson M, Schell H, Kahle PJ, Moller C, Gellerfors P, Bergstrom J, Lannfelt L and Ingelsson M (2014). Immunotherapy targeting alpha-synuclein protofibrils reduced pathology in (Thy-1)-h[A30P] alpha-synuclein mice. Neurobiol Dis. 69: 134-43.

Lindstrom V, Ihse E, Fagerqvist T, Bergstrom J, Nordstrom E, Moller C, Lannfelt L and Ingelsson M (2014). Immunotherapy targeting alpha-synuclein, with relevance for future treatment of Parkinson's disease and other Lewy body disorders. Immunotherapy. 6: 141-53.

Fagerqvist T, Nasstrom T, Ihse E, Lindstrom V, Sahlin C, Tucker SM, Kasaryan A, Karlsson M, Nikolajeff F, Schell H, Outeiro TF, Kahle PJ, Lannfelt L, Ingelsson M and Bergstrom J (2013). Off-pathway alpha-synuclein oligomers seem to alter alpha-synuclein turnover in a cell model but lack seeding capability in vivo. Amyloid. 20: 233-44.

Fagerqvist T, Lindstrom V, Nordstrom E, Lord A, Tucker SM, Su X, Sahlin C, Kasrayan A, Andersson J, Welander H, Nasstrom T, Holmquist M, Schell H, Kahle PJ, Kalimo H, Moller C, Gellerfors P, Lannfelt L, Bergstrom J and Ingelsson M (2013). Monoclonal antibodies selective for alpha-synuclein oligomers/protofibrils recognize brain pathology in Lewy body disorders and alpha-synuclein transgenic mice with the disease-causing A30P mutation. J Neurochem. 126: 131-44.

Nasstrom T, Goncalves S, Sahlin C, Nordstrom E, Screpanti Sundquist V, Lannfelt L, Bergstrom J, Outeiro TF and Ingelsson M (2011). Antibodies against alpha-synuclein reduce oligomerization in living cells. PLoS One. 6: e27230.

Nasstrom T, Fagerqvist T, Barbu M, Karlsson M, Nikolajeff F, Kasrayan A, Ekberg M, Lannfelt L, Ingelsson M and Bergstrom J (2011). The lipid peroxidation products 4-oxo-2-nonenal and 4-hydroxy-2-nonenal promote the formation of alpha-synuclein oligomers with distinct biochemical, morphological, and functional properties. Free Radic Biol Med. 50: 428-37.