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SOD1 prions transmit templated aggregation and fatal ALS-like disease
Umeå University, Faculty of Medicine, Department of Medical Biosciences. (ALS Group)ORCID iD: 0000-0002-3787-7629
2019 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Amyotrophic lateral sclerosis (ALS) is an adult-onset fatal neurodegenerative disease characterized by a progressive degeneration of the upper and lower motor neurons. The resulting paresis begins focally, usually in one muscle, and spreads contiguously, leading to muscle wasting, progressive paralysis and eventually death. 90% of all ALS cases are sporadic, with no genetic background (sALS), while 10% are hereditary or familial (fALS). The first identified cause of ALS was mutations in the gene encoding the enzyme superoxide dismutase 1 (SOD1), which are found in 3-6% of the ALS patients. Mutations in SOD1 confer a cytotoxic gain of function on the enzyme. Cytosolic inclusions containing aggregated SOD1 in motor neurons are a hallmark of ALS, both in patients and transgenic (Tg) mice carrying mutant human SOD1s (hSOD1). These inclusions have also been reported in sporadic and familial ALS cases without SOD1 mutations, suggesting a broader role of this protein in the ALS pathology. However, the mechanism of SOD1 misfolding and aggregation, and their contribution to the disease pathogenesis, is unclear.

Our research group has recently identified two structurally different strains of hSOD1 aggregates (denoted A and B) in the central nervous system of Tg murine models expressing full-length hSOD1 variants.

The aim of this thesis is to investigate if the SOD1 aggregation is a collateral byproduct in the process of the disease, or if it drives ALS pathogenesis. In addition, this work investigates the spreading characteristic of the disease in vivo.

Human SOD1 A and B seeds were prepared from spinal cords of terminally ill hSOD1 Tg mice by ultracentrifugation through a density gradient. Minute amounts of the aggregate seeds were micro-inoculated into the lumbar spinal cord of asymptomatic recipient Tg mice, overexpressing G85R mutant hSOD1 (hSOD1G85R). Mice inoculated with A or B aggregates developed early-onset fatal ALS-like disease, becoming terminally ill around 100 days after inoculation. This is nearly 200 days earlier than hSOD1G85R Tg mice inoculated with a control preparation or non-inoculated mice. Concomitantly, exponentially growing templated hSOD1 aggregation developed in the recipient mice, spreading all along the neuraxis. The pathology provoked by the A and B strains differed in aggregation growth rates, disease progression rates, aggregate distribution along the neuraxis, rates of weight loss, end-stage amounts of aggregates, and histopathology.

Next, we explored the existence of mutant hSOD1 aggregates with prion-like properties in the spinal cord of ALS patients.  To this end, aggregate seeds were prepared from the spinal cord of the autopsy material of an ALS patient carrying the hSOD1G127X truncation mutation, as well as from mice transgenic for the same mutation. The aggregates showed a strain A-like core structure. Inoculation of both the murine and human derived seeds into the lumbar spinal cord of hSOD1 expressing mice efficiently transmitted strain A aggregation, propagating rostrally throughout the neuraxis and causing premature fatal ALS-like disease. The inoculation of human or murine control seeds had no effect. The potency of the ALS patient-derived seed was exceedingly high, and the disease was initiated under conditions plausible to exist also in the human motor system. These results demonstrate for the first time, the presence of hSOD1 aggregates with prion-like properties in human ALS.

We extended the exploration of hSOD1 prion mechanisms by inoculating another recipient mouse line, with wild-type-like stability and essentially normal SOD activity. Mice that are hemizygous for the hSOD1D90A transgene insertion do not develop ALS pathology and have normal murine lifespans (>700 days). Homozygous mice develop ALS-like disease around 400 days-of-age. Interestingly, inoculations of both strain A and B seeds into the lumbar spinal cord of hemizygous hSOD1D90A mice induced progressive hSOD1 aggregations and premature fatal ALS-like disease after around 250 and 350 days, respectively. In contrast, hemizygous hSOD1D90A mice inoculated with a mouse control seed died from senescence-related causes at ages beyond 700 days.

Altogether, data in this thesis shows that the hSOD1 aggregate strains are ALS transmitting prions, suggesting that prion-like growth and spread of hSOD1 aggregation is the core pathogenic mechanism of SOD1-induced ALS.

Place, publisher, year, edition, pages
Umeå: Umeå Universitet , 2019. , p. 70
Series
Umeå University medical dissertations, ISSN 0346-6612 ; 2047
Keywords [en]
ALS, amyotrophic lateral sclerosis, SOD1, prion, neurodegeneration, strain, seeding, protein misfolding, protein aggregation, propagation, transgenic mice
National Category
Neurosciences Neurology
Research subject
Pathology; Neurology
Identifiers
URN: urn:nbn:se:umu:diva-163291ISBN: 978-91-7855-106-4 (print)OAI: oai:DiVA.org:umu-163291DiVA, id: diva2:1350941
Public defence
2019-10-11, E04, R-1, Norrlands Universitetssjukhus, byggnad 6E, Umeå, 13:00 (English)
Opponent
Supervisors
Available from: 2019-09-20 Created: 2019-09-12 Last updated: 2019-09-18Bibliographically approved
List of papers
1. Two superoxide dismutase prion strains transmit amyotrophic lateral sclerosis-like disease
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2016 (English)In: Journal of Clinical Investigation, ISSN 0021-9738, E-ISSN 1558-8238, Vol. 126, no 6, p. 2249-2253Article in journal (Refereed) Published
Abstract [en]

Amyotrophic lateral sclerosis (ALS) is an adult-onset degeneration of motor neurons that is commonly caused by mutations in the gene encoding superoxide dismutase 1 (SOD1). Both patients and Tg mice expressing mutant human SOD1 (hSOD1) develop aggregates of unknown importance. In Tg mice, 2 different strains of hSOD1 aggregates (denoted A and B) can arise; however, the role of these aggregates in disease pathogenesis has not been fully characterized. Here, minute amounts of strain A and B hSOD1 aggregate seeds that were prepared by centrifugation through a density cushion were inoculated into lumbar spinal cords of 100-day-old mice carrying a human SOD1 Tg. Mice seeded with A or B aggregates developed premature signs of ALS and became terminally ill after approximately 100 days, which is 200 days earlier than for mice that had not been inoculated or were given a control preparation. Concomitantly, exponentially growing strain A and B hSOD1 aggregations propagated rostrally throughout the spinal cord and brainstem. The phenotypes provoked by the A and B strains differed regarding progression rates, distribution, end-stage aggregate levels, and histopathology. Together, our data indicate that the aggregate strains are prions that transmit a templated, spreading aggregation of hSOD1, resulting in a fatal ALS-like disease.

National Category
Medical Bioscience Neurosciences
Identifiers
urn:nbn:se:umu:diva-122554 (URN)10.1172/JCI84360 (DOI)000377027500021 ()27140399 (PubMedID)
Available from: 2016-07-25 Created: 2016-06-20 Last updated: 2019-09-12Bibliographically approved
2. Mutant superoxide dismutase aggregates from human spinal cord transmit amyotrophic lateral sclerosis
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2018 (English)In: Acta Neuropathologica, ISSN 0001-6322, E-ISSN 1432-0533, Vol. 136, no 6, p. 939-953Article in journal (Refereed) Published
Abstract [en]

Motor neurons containing aggregates of superoxide dismutase 1 (SOD1) are hallmarks of amyotrophic lateral sclerosis (ALS) caused by mutations in the gene encoding SOD1. We have previously reported that two strains of mutant human (h) SOD1 aggregates (denoted A and B) can arise in hSOD1-transgenic models for ALS and that inoculation of such aggregates into the lumbar spinal cord of mice results in rostrally spreading, templated hSOD1 aggregation and premature fatal ALS-like disease. Here, we explored whether mutant hSOD1 aggregates with prion-like properties also exist in human ALS. Aggregate seeds were prepared from spinal cords from an ALS patient carrying the hSOD1G127Gfs*7 truncation mutation and from mice transgenic for the same mutation. To separate from mono-, di- or any oligomeric hSOD1 species, the seed preparation protocol included ultracentrifugation through a density cushion. The core structure of hSOD1G127Gfs*7 aggregates present in mice was strain A-like. Inoculation of the patient- or mouse-derived seeds into lumbar spinal cord of adult hSOD1-expressing mice induced strain A aggregation propagating along the neuraxis and premature fatal ALS-like disease (p < 0.0001). Inoculation of human or murine control seeds had no effect. The potencies of the ALS patient-derived seed preparations were high and disease was initiated in the transgenic mice by levels of hSOD1G127Gfs*7 aggregates much lower than those found in the motor system of patients carrying the mutation. The results suggest that prion-like growth and spread of hSOD1 aggregation could be the primary pathogenic mechanism, not only in hSOD1 transgenic rodent models, but also in human ALS.

Place, publisher, year, edition, pages
Springer, 2018
Keywords
Superoxide dismutase, prion-like, aggregation, propagation, motor neuron disease
National Category
Neurosciences
Research subject
Neurology; Pathology
Identifiers
urn:nbn:se:umu:diva-150909 (URN)10.1007/s00401-018-1915-y (DOI)000451952700008 ()30284034 (PubMedID)
Funder
Knut and Alice Wallenberg FoundationTorsten Söderbergs stiftelseThe Swedish Brain FoundationThe Kempe FoundationsVästerbotten County Council
Note

Originally included in thesis in manuscript form.

Available from: 2018-08-18 Created: 2018-08-18 Last updated: 2019-09-12Bibliographically approved
3. Superoxide dismutase prions transmit fatal ALS to transgenic mice which do not spontaneously develop symptoms
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(English)Manuscript (preprint) (Other academic)
National Category
Neurosciences
Identifiers
urn:nbn:se:umu:diva-163396 (URN)
Available from: 2019-09-18 Created: 2019-09-18 Last updated: 2019-09-18

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Ekhtiari Bidhendi, Elaheh

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