Research of professor Peter M. Andersen, MD, PhD
Overview: MD 1990, PhD 1997, Specialist neurologist 1997, Post-doc medical research fellow 1998-1999, Assistant professor of Neurology 2000, Professor of Neurology 2010. Wallenberg Clinical Scholar 2015-2020. Starting date at Umeå University/University Hospital of northern Sweden: June 1st., 1992 Research Group: The ALS-FTD Research Group Research interest: clinical, molecular and cellular studies in the familial and sporadic motor neuron diseases (ALS) with or without dementia (FTD)
The ALS-FTD research group at the Institute of Clinical Neuroscience was created in 1992 and is an integral key part of the larger ALS-FTD Neurodegenerative Research Consortium at Umeå University that today comprises 5 other groups. Combined, the collaborative research of the multidiciplinary groups has been very successful with more than 170 publications including 8 in Nature journals.
The ALS-FTD research group has for more than 23 years performed a variety of clinical bedside studies including the only clinical trial of riluzole performed in northern Europe, the introduction of X-ray irradiation of the salivary glands to reduce drooling in patients with troublesome dysphagia as well as ongoing studies of the genetics of ALS genetic-epidemiology in four European countries (ONWEBDUALS, an EU sponsored JPND 2014-Project) and the difficult issues and decisions patients with ALS and their relatives faces (NEEDS/ELISA, an EU sponsored JPND 2013-Project).
The main emphasis is however on - by studying the many genetic variants predisposing to ALS - to get insight into the underlying molecular pathogenesis and thereby develop new strategies for more effective therapies. The basis for this is the collecting of blood, CSF, skin biopsies and whenever possible autopsies from patients with ALS/FTD and perform extensive genetic and molecular analysis. This biobanking is performed by a network of collaborators across Europe.
The Umeå ALS Research Consortium performs a wide variety of molecular, cellular, genetic and human bed-side studies. In summary, we find that:
- All identified ALS-causing genes are pleiotropic and can in an individual patient give rise to a uniform phenotype or mixed phenotype (i.e. ALS with FTD, ALS with ataxia etc.). Over 32 ALS-genes have been identified since 1993;
- Studying families with mutated genes, we find that while there in some families is complete penetrance, more common is reduced disease penetrance. This shows that other factors than the primary mutant gene are involved. Since the penetrance is low in some SOD1, FUS and C9orf72 families, these must be biologically powerful factors;
- Clinical analysis of these pedigrees suggest that the three parameters age of onset, disease progression rate and disease penetrance are independent variables. Identifying the biology behind may open up pathways for new therapies and possibly also for preventive measures;
- All autopsied ALS patients independent of genotype contain inclusions of misfolded SOD1 (misSOD1). Ongoing analysis of 16 human autopsies with SOD1 mutations show that wtSOD1 is also misfolded and is part of these aggregates;
- Using a novel binary epitope-mapping assay we have found that at least 2 different strains of hSOD1 fibrils/aggregates (“A” and “B”), associated with different disease progressions, are acting in hSOD1 transgenic mice. Human SOD1 aggregates, generated in vitro under a variety of conditions, were all different from the aggregates strains that form in vivo. This shows that cells restrict aggregation pathways and that the outcome of this control might determine type and severity of ALS.
We propose that in ALS, unfolded SOD1 species gain self-propagating conformations that can transmit to other cells and in these induce further replication of distinct strains of misSOD1. This self-propagating templated action of misSOD1 is cytotoxic and may involve the formation of SOD1 microfibrils and SOD1 aggregates. This prion hypothesis is in line with what has recently emerged from studies in AD and PD. Research by us and others suggest that the major neurodegenerative diseases share a number of features:
- Adult insidious clinical onset of pathology initally in specific populations of neurons, later to become more generalized;
- In ALS as in PD and AD, 5-10% of patients report a familial predisposition; several mutated genes have been identified (e.g., APP in AD, a-synuclein in PD, SOD1 in ALS); hallmarks of families are the frequent occurrence of reduced disease penetrance and variable expression phenotype;
- The mutant protein (asynuclein in some PD, SOD1 in some ALS) misfold forming oligomers and aggregates. The mutant protein gains prionic properties and transmit through the CNS;
- The aggregates containing the protein found mutated in some familial cases, are also found in patients without such mutations but with a similar phenotype (aggregates of misfolded wt-asynuclein appears in all variants of PD, of wt-Ab in AD, and of wtSOD1 in all types of ALS);
- In AD, PD and ALS, respectively, distinct strains of wt-Ab, wt-asynuclein or wt-SOD1 becomes prionic by inducing templated misfolding of wt-species and transmission to other cells;
- The median age of appearance of first clinical symptoms is lower in patients carrying mutations in the primary disease-causing gene (i.e. SOD1 for ALS, a-synuclein for PD) than in patients carrying mutations in other genes resulting in a similar phenotype (e.g., C9orf72, OPTN, TDP-43 for ALS), which in turn have a younger onset age than patients with sporadic disease.
These observations generate two critical questions:
- In patients carrying whole genomic mutations in APP, asynuclein or SOD1, what factor(s) compensate or protects for the pathogenic process first resulting in disease symptoms in mid-life?
- In patients without such mutations, what destabilizes wt-Ab, wt-asynuclein or wt-SOD1 in late life causing unfolding and polymerization to distinct toxic species with self-propagating properties?
The recent evidence that AD, PD, MSA and ALS all have features of being prion diseases is a paradigm shift. If proved, it open up avenues for new therapeutic concepts as well as for preventive measures in at-risk individuals carrying predisposing mutations. In the case of ALS this could be by reducing the cellular load of SOD1 by blocking transcription and/or translation and by inhibition the seeding of misSOD1. Further insight into the early biology of ALS and the role of SOD1 is essential.
Some of our ongoing projects (fall of 2015) includes:
1. Study SOD1 seeding in vivo,
2. Study SOD1 seeding in vitro in iPS cell culture systems,
3. Study compromised proteostasis of SOD1, TBK1, OPTN, p62, TDP43 and FUS,
4. Interventions to block transmission of SOD1 prions,
5. Studying SOD1 aggregate strains in different types of ALS.
6. Searching for novel ALS-FTD causing gene defects as well as neuroprotective modifiers.
Recent major output:
Freischmidt A, Wieland T, Richter B, Ruf W, Veronique Schäffer V, Müller K, Marroquin N, Frida Nordin F, Hübers A, Weydt P, Susana Pinto S, Press R, Millicamps Stéphanie, Molko N, Bernard E, Desnuelle C, Soriani M-H, Dorst J, Graf E, Nordström U, Feiler MS, Putz S, Böckers TM, Meyer T, Winkler AS, Winkelman J, de Carvalho M, Thal DR, Otto M, Brännström T, Volk AE, Kursula P, Danzer KM, Lichtner P, Dikic I, Meitinger T, Ludolph AC, Strom TM*, Andersen PM*, Weishaupt JH*. Haploinssuficiency of TBK1 causes amyotrophic lateral sclerosis and fronto-temporal dementia. *Shared last authors
Nat Neurosci May 2015;18:631-636.
Knut and Alice Wallenberg Foundation (KAW)
Swedish Brain Power I and II
The Erling-Persson Foundation
Ulla-Carin Lindquist Foundation
The Torsten Söderberg Foundation
The Carl Kempe Foundation
The Brain Research Foundation (Sweden)
The Science Council (Sweden)
The European Union (JPND 2013, 2014)
Neuroförbundet (patient organization)
Västerbotten County Council