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LAS VEGAS—Significant commonalities between multiple system atrophy (MSA) and Parkinson’s disease suggest that knowledge about the latter disorder could help direct research into the former, according to an overview provided at the recent Global MSA Research Roadmap Meeting. But despite their neuropathologic and symptomatic similarities, MSA and Parkinson’s disease are notably different diseases, researchers said.
MSA is a rare but fatal adult-onset neurodegenerative disorder of uncertain etiology. It is characterized by features such as autonomic failure and parkinsonism and, like Parkinson’s disease, is marked by the deposition of abnormally phosphorylated α-synuclein.
Biomarkers and Therapeutic Targets
Of all of the features of Parkinson’s disease, the pathogenic cascade may have the most potential for guiding future research into MSA, said Patrik Brundin, MD, PhD, Director of the Center for Neurodegenerative Science at the Van Andel Research Institute in Grand Rapids, Michigan. Although the primary aspects of pathogenesis distinguish the two diseases, the latter share several secondary phenomena such as proinflammatory mechanisms. These phenomena could be useful in the development of biomarkers and therapeutic targets. Knowledge about the pathogenic cascade in Parkinson’s disease, however, is limited.
“We don’t really understand Parkinson’s disease pathogenesis,” said Dr. Brundin. “We are painfully ignorant … We still don’t really know what causes the cell death and the degeneration. But we can ask the question, ‘Is it likely to be similar to MSA?’”
Research by Jellinger, Kuzdas-Wood, and others has prompted investigators to propose a five-part pathogenic cascade for MSA. The cascade begins with the healthy neuron and glial cell until the oligodendrocytes “get sick,” which results in neuronal degeneration, said Dr. Brundin. The next part encompasses α-synuclein accumulation in the oligodendroglial cytoplasm, followed by “failure of mitochondrial function, loss of trophic factor support, possible loss of proteosomal function, and increased oxidative stress.” In the following step, oligodendroglia degenerate, and the final phase involves secondary neuronal loss accompanied by microglial and astroglial activation.
Several factors have been implicated in Parkinson’s disease, but researchers are uncertain about which ones are important, said Dr. Brundin. Krismer et al enumerated distinguishing and overlapping features of MSA and Parkinson’s disease. The pathogenic element that distinguishes MSA from Parkinson’s disease is the oligodendrocyte pathology, “possibly this p25 alpha transportation to membrane, and then, as a secondary event, the neurons dying,” said Dr. Brundin. Parkinson’s disease probably starts with synaptic pathology and proceeds with retrograde degeneration toward the cell body, he added.
Treatment options for MSA are limited and mainly provide symptomatic relief. No therapies modify the disease. The development of new biomarkers could enable earlier diagnosis and allow treatment to begin at symptom onset, which is when disease severity is lower. “We desperately need biomarkers,” said Dr. Brundin.
Potential biomarkers include α-synuclein imaging and MRI morphometry; neuroinflammation imaging; and blood, plasma, and CSF biomarkers for inflammation, α-synuclein, and other proteins.
Knowledge about Parkinson’s disease may be of little help in the development of disease-modifying therapies for MSA, said Dr. Brundin. “Considering that there is still no drug that’s been proven to slow the progression of Parkinson’s disease, how on Earth are we going to be able to use any information from that field of research in MSA? Hopefully, in the future there will be a drug that slows the progression of Parkinson’s disease.”
The strategy of targeting extracellular α-synuclein and emerging data on neuroinflammation in Parkinson’s disease could be relevant to MSA research. “If we get a drug that enhances mitochondrial function … perhaps it can be used in MSA,” said Dr. Brundin. Glial cell line‐derived neurotrophic factor, which has been tested with limited success in Parkinson’s disease, might be a better therapy for MSA, he added.
Protein Handling or Misfolding
Although α-synuclein misfolding does not occur in the same way in Parkinson’s disease and MSA, the diseases share enough similarities to make the process one of the more important things that researchers who study MSA have learned from Parkinson’s disease, said Ronald Melki, PhD, Director of Research at the Laboratoire d’Enzymologie et Biochemie Structurales of the Centre National de la Recherche Scientifique in Gif-sur-Yvette, France.
The misfolding process begins when newly synthesized proteins unfold in cells or are degraded incorrectly. This occurrence populates folding intermediates that assemble in fibrillar aggregates, which are the hallmark of various neurodegenerative diseases. Primary neurons take up fibrillar α-synuclein and transport it through the axon, and second-order neurons ultimately internalize it, explained Dr. Melki. “This [process] suggests that these aggregates are propagating within our brain in a manner reminiscent of prion protein propagation.”
One unanswered question with implications for future research is whether Parkinson’s disease and MSA are the consequences of distinct strains of α-synuclein. “I have a tendency … to answer ‘yes’ because we have one protein [that is] assembled into two different forms that have two different molecular codes,” said Dr. Melki. Electron microscopy shows that one form of the protein resembles spaghetti and the other resembles linguine. “These two fibrils are getting a different sort of pathology or different distribution in the brain. So, we think that we have strains that are distinct structurally and functionally—exactly what people have described ... in the prion field.”
Investigators must use methods developed for prion research, such as amplification of protein assemblies from patients through sonication, added Dr. Melki. In a recent study conducted with colleagues from Bordeaux, he obtained samples from patients who developed disease and amplified the assemblies in test tubes. The process resulted in fibrils that the investigators will inject into animals to evaluate whether they reproduce the distinct diseases.
—Fred Balzac
Suggested Reading
Bousset L, Pieri L, Ruiz-Arlandis G, et al. Structural and functional characterization of two alpha-synuclein strains. Nat Commun. 2013;4:2575.
Brundin P, Melki R, Kopito R. Prion-like transmission of protein aggregates in neurodegenerative diseases. Nat Rev Mol Cell Biol. 2010;11(4):301-307.
Halliday GM, Holton JL, Revesz T, et al. Neuropathology underlying clinical variability in patients with synucleinopathies. Acta Neuropathol. 2011;122(2):187-204.
Jellinger KA. Neuropathology of multiple system atrophy: new thoughts about pathogenesis. Mov Disord. 2014;29(14):1720-1741.
Krismer F, Jellinger KA, Scholz SW, et al. Multiple system atrophy as emerging template for accelerated drug discovery in α-synucleinopathies. Parkinsonism Relat Disord. 2014;20(8):793-799.
Kuzdas-Wood D, Stefanova N, Jellinger KA, et al. Towards translational therapies for multiple system atrophy. Prog Neurobiol. 2014;118:19-35.
National Library of Medicine (US). Genetics Home Reference [Internet]. Bethesda (MD): The Library; 2014 Dec 22. Multiple system atrophy; [reviewed 2012 Jan; cited 2014 Dec 27]. Available at: http://ghr.nlm.nih.gov/condition/multiple-system-atrophy.
Nonnekes J, Aerts MB, Abdo WF, Bloem BR. Medio-lateral balance impairment differentiates between Parkinson’s disease and atypical parkinsonism. J Parkinsons Dis. 2014;4(4):567-569.
Reyes JF, Rey NL, Bousset L, et al. Alpha-synuclein transfers from neurons to oligodendrocytes. Glia. 2014;62(3):387-398.
Scholz SW, Houlden H, Schulte C, et al. SNCA variants are associated with increased risk for multiple system atrophy. Ann Neurol. 2009;65(5):610-614.
Sieber BA, Landis S, Koroshetz W, et al. Prioritized research recommendations from the National Institute of Neurological Disorders and Stroke Parkinson's Disease 2014 conference. Ann Neurol. 2014;76(4):469-472.
LAS VEGAS—Significant commonalities between multiple system atrophy (MSA) and Parkinson’s disease suggest that knowledge about the latter disorder could help direct research into the former, according to an overview provided at the recent Global MSA Research Roadmap Meeting. But despite their neuropathologic and symptomatic similarities, MSA and Parkinson’s disease are notably different diseases, researchers said.
MSA is a rare but fatal adult-onset neurodegenerative disorder of uncertain etiology. It is characterized by features such as autonomic failure and parkinsonism and, like Parkinson’s disease, is marked by the deposition of abnormally phosphorylated α-synuclein.
Biomarkers and Therapeutic Targets
Of all of the features of Parkinson’s disease, the pathogenic cascade may have the most potential for guiding future research into MSA, said Patrik Brundin, MD, PhD, Director of the Center for Neurodegenerative Science at the Van Andel Research Institute in Grand Rapids, Michigan. Although the primary aspects of pathogenesis distinguish the two diseases, the latter share several secondary phenomena such as proinflammatory mechanisms. These phenomena could be useful in the development of biomarkers and therapeutic targets. Knowledge about the pathogenic cascade in Parkinson’s disease, however, is limited.
“We don’t really understand Parkinson’s disease pathogenesis,” said Dr. Brundin. “We are painfully ignorant … We still don’t really know what causes the cell death and the degeneration. But we can ask the question, ‘Is it likely to be similar to MSA?’”
Research by Jellinger, Kuzdas-Wood, and others has prompted investigators to propose a five-part pathogenic cascade for MSA. The cascade begins with the healthy neuron and glial cell until the oligodendrocytes “get sick,” which results in neuronal degeneration, said Dr. Brundin. The next part encompasses α-synuclein accumulation in the oligodendroglial cytoplasm, followed by “failure of mitochondrial function, loss of trophic factor support, possible loss of proteosomal function, and increased oxidative stress.” In the following step, oligodendroglia degenerate, and the final phase involves secondary neuronal loss accompanied by microglial and astroglial activation.
Several factors have been implicated in Parkinson’s disease, but researchers are uncertain about which ones are important, said Dr. Brundin. Krismer et al enumerated distinguishing and overlapping features of MSA and Parkinson’s disease. The pathogenic element that distinguishes MSA from Parkinson’s disease is the oligodendrocyte pathology, “possibly this p25 alpha transportation to membrane, and then, as a secondary event, the neurons dying,” said Dr. Brundin. Parkinson’s disease probably starts with synaptic pathology and proceeds with retrograde degeneration toward the cell body, he added.
Treatment options for MSA are limited and mainly provide symptomatic relief. No therapies modify the disease. The development of new biomarkers could enable earlier diagnosis and allow treatment to begin at symptom onset, which is when disease severity is lower. “We desperately need biomarkers,” said Dr. Brundin.
Potential biomarkers include α-synuclein imaging and MRI morphometry; neuroinflammation imaging; and blood, plasma, and CSF biomarkers for inflammation, α-synuclein, and other proteins.
Knowledge about Parkinson’s disease may be of little help in the development of disease-modifying therapies for MSA, said Dr. Brundin. “Considering that there is still no drug that’s been proven to slow the progression of Parkinson’s disease, how on Earth are we going to be able to use any information from that field of research in MSA? Hopefully, in the future there will be a drug that slows the progression of Parkinson’s disease.”
The strategy of targeting extracellular α-synuclein and emerging data on neuroinflammation in Parkinson’s disease could be relevant to MSA research. “If we get a drug that enhances mitochondrial function … perhaps it can be used in MSA,” said Dr. Brundin. Glial cell line‐derived neurotrophic factor, which has been tested with limited success in Parkinson’s disease, might be a better therapy for MSA, he added.
Protein Handling or Misfolding
Although α-synuclein misfolding does not occur in the same way in Parkinson’s disease and MSA, the diseases share enough similarities to make the process one of the more important things that researchers who study MSA have learned from Parkinson’s disease, said Ronald Melki, PhD, Director of Research at the Laboratoire d’Enzymologie et Biochemie Structurales of the Centre National de la Recherche Scientifique in Gif-sur-Yvette, France.
The misfolding process begins when newly synthesized proteins unfold in cells or are degraded incorrectly. This occurrence populates folding intermediates that assemble in fibrillar aggregates, which are the hallmark of various neurodegenerative diseases. Primary neurons take up fibrillar α-synuclein and transport it through the axon, and second-order neurons ultimately internalize it, explained Dr. Melki. “This [process] suggests that these aggregates are propagating within our brain in a manner reminiscent of prion protein propagation.”
One unanswered question with implications for future research is whether Parkinson’s disease and MSA are the consequences of distinct strains of α-synuclein. “I have a tendency … to answer ‘yes’ because we have one protein [that is] assembled into two different forms that have two different molecular codes,” said Dr. Melki. Electron microscopy shows that one form of the protein resembles spaghetti and the other resembles linguine. “These two fibrils are getting a different sort of pathology or different distribution in the brain. So, we think that we have strains that are distinct structurally and functionally—exactly what people have described ... in the prion field.”
Investigators must use methods developed for prion research, such as amplification of protein assemblies from patients through sonication, added Dr. Melki. In a recent study conducted with colleagues from Bordeaux, he obtained samples from patients who developed disease and amplified the assemblies in test tubes. The process resulted in fibrils that the investigators will inject into animals to evaluate whether they reproduce the distinct diseases.
—Fred Balzac
LAS VEGAS—Significant commonalities between multiple system atrophy (MSA) and Parkinson’s disease suggest that knowledge about the latter disorder could help direct research into the former, according to an overview provided at the recent Global MSA Research Roadmap Meeting. But despite their neuropathologic and symptomatic similarities, MSA and Parkinson’s disease are notably different diseases, researchers said.
MSA is a rare but fatal adult-onset neurodegenerative disorder of uncertain etiology. It is characterized by features such as autonomic failure and parkinsonism and, like Parkinson’s disease, is marked by the deposition of abnormally phosphorylated α-synuclein.
Biomarkers and Therapeutic Targets
Of all of the features of Parkinson’s disease, the pathogenic cascade may have the most potential for guiding future research into MSA, said Patrik Brundin, MD, PhD, Director of the Center for Neurodegenerative Science at the Van Andel Research Institute in Grand Rapids, Michigan. Although the primary aspects of pathogenesis distinguish the two diseases, the latter share several secondary phenomena such as proinflammatory mechanisms. These phenomena could be useful in the development of biomarkers and therapeutic targets. Knowledge about the pathogenic cascade in Parkinson’s disease, however, is limited.
“We don’t really understand Parkinson’s disease pathogenesis,” said Dr. Brundin. “We are painfully ignorant … We still don’t really know what causes the cell death and the degeneration. But we can ask the question, ‘Is it likely to be similar to MSA?’”
Research by Jellinger, Kuzdas-Wood, and others has prompted investigators to propose a five-part pathogenic cascade for MSA. The cascade begins with the healthy neuron and glial cell until the oligodendrocytes “get sick,” which results in neuronal degeneration, said Dr. Brundin. The next part encompasses α-synuclein accumulation in the oligodendroglial cytoplasm, followed by “failure of mitochondrial function, loss of trophic factor support, possible loss of proteosomal function, and increased oxidative stress.” In the following step, oligodendroglia degenerate, and the final phase involves secondary neuronal loss accompanied by microglial and astroglial activation.
Several factors have been implicated in Parkinson’s disease, but researchers are uncertain about which ones are important, said Dr. Brundin. Krismer et al enumerated distinguishing and overlapping features of MSA and Parkinson’s disease. The pathogenic element that distinguishes MSA from Parkinson’s disease is the oligodendrocyte pathology, “possibly this p25 alpha transportation to membrane, and then, as a secondary event, the neurons dying,” said Dr. Brundin. Parkinson’s disease probably starts with synaptic pathology and proceeds with retrograde degeneration toward the cell body, he added.
Treatment options for MSA are limited and mainly provide symptomatic relief. No therapies modify the disease. The development of new biomarkers could enable earlier diagnosis and allow treatment to begin at symptom onset, which is when disease severity is lower. “We desperately need biomarkers,” said Dr. Brundin.
Potential biomarkers include α-synuclein imaging and MRI morphometry; neuroinflammation imaging; and blood, plasma, and CSF biomarkers for inflammation, α-synuclein, and other proteins.
Knowledge about Parkinson’s disease may be of little help in the development of disease-modifying therapies for MSA, said Dr. Brundin. “Considering that there is still no drug that’s been proven to slow the progression of Parkinson’s disease, how on Earth are we going to be able to use any information from that field of research in MSA? Hopefully, in the future there will be a drug that slows the progression of Parkinson’s disease.”
The strategy of targeting extracellular α-synuclein and emerging data on neuroinflammation in Parkinson’s disease could be relevant to MSA research. “If we get a drug that enhances mitochondrial function … perhaps it can be used in MSA,” said Dr. Brundin. Glial cell line‐derived neurotrophic factor, which has been tested with limited success in Parkinson’s disease, might be a better therapy for MSA, he added.
Protein Handling or Misfolding
Although α-synuclein misfolding does not occur in the same way in Parkinson’s disease and MSA, the diseases share enough similarities to make the process one of the more important things that researchers who study MSA have learned from Parkinson’s disease, said Ronald Melki, PhD, Director of Research at the Laboratoire d’Enzymologie et Biochemie Structurales of the Centre National de la Recherche Scientifique in Gif-sur-Yvette, France.
The misfolding process begins when newly synthesized proteins unfold in cells or are degraded incorrectly. This occurrence populates folding intermediates that assemble in fibrillar aggregates, which are the hallmark of various neurodegenerative diseases. Primary neurons take up fibrillar α-synuclein and transport it through the axon, and second-order neurons ultimately internalize it, explained Dr. Melki. “This [process] suggests that these aggregates are propagating within our brain in a manner reminiscent of prion protein propagation.”
One unanswered question with implications for future research is whether Parkinson’s disease and MSA are the consequences of distinct strains of α-synuclein. “I have a tendency … to answer ‘yes’ because we have one protein [that is] assembled into two different forms that have two different molecular codes,” said Dr. Melki. Electron microscopy shows that one form of the protein resembles spaghetti and the other resembles linguine. “These two fibrils are getting a different sort of pathology or different distribution in the brain. So, we think that we have strains that are distinct structurally and functionally—exactly what people have described ... in the prion field.”
Investigators must use methods developed for prion research, such as amplification of protein assemblies from patients through sonication, added Dr. Melki. In a recent study conducted with colleagues from Bordeaux, he obtained samples from patients who developed disease and amplified the assemblies in test tubes. The process resulted in fibrils that the investigators will inject into animals to evaluate whether they reproduce the distinct diseases.
—Fred Balzac
Suggested Reading
Bousset L, Pieri L, Ruiz-Arlandis G, et al. Structural and functional characterization of two alpha-synuclein strains. Nat Commun. 2013;4:2575.
Brundin P, Melki R, Kopito R. Prion-like transmission of protein aggregates in neurodegenerative diseases. Nat Rev Mol Cell Biol. 2010;11(4):301-307.
Halliday GM, Holton JL, Revesz T, et al. Neuropathology underlying clinical variability in patients with synucleinopathies. Acta Neuropathol. 2011;122(2):187-204.
Jellinger KA. Neuropathology of multiple system atrophy: new thoughts about pathogenesis. Mov Disord. 2014;29(14):1720-1741.
Krismer F, Jellinger KA, Scholz SW, et al. Multiple system atrophy as emerging template for accelerated drug discovery in α-synucleinopathies. Parkinsonism Relat Disord. 2014;20(8):793-799.
Kuzdas-Wood D, Stefanova N, Jellinger KA, et al. Towards translational therapies for multiple system atrophy. Prog Neurobiol. 2014;118:19-35.
National Library of Medicine (US). Genetics Home Reference [Internet]. Bethesda (MD): The Library; 2014 Dec 22. Multiple system atrophy; [reviewed 2012 Jan; cited 2014 Dec 27]. Available at: http://ghr.nlm.nih.gov/condition/multiple-system-atrophy.
Nonnekes J, Aerts MB, Abdo WF, Bloem BR. Medio-lateral balance impairment differentiates between Parkinson’s disease and atypical parkinsonism. J Parkinsons Dis. 2014;4(4):567-569.
Reyes JF, Rey NL, Bousset L, et al. Alpha-synuclein transfers from neurons to oligodendrocytes. Glia. 2014;62(3):387-398.
Scholz SW, Houlden H, Schulte C, et al. SNCA variants are associated with increased risk for multiple system atrophy. Ann Neurol. 2009;65(5):610-614.
Sieber BA, Landis S, Koroshetz W, et al. Prioritized research recommendations from the National Institute of Neurological Disorders and Stroke Parkinson's Disease 2014 conference. Ann Neurol. 2014;76(4):469-472.
Suggested Reading
Bousset L, Pieri L, Ruiz-Arlandis G, et al. Structural and functional characterization of two alpha-synuclein strains. Nat Commun. 2013;4:2575.
Brundin P, Melki R, Kopito R. Prion-like transmission of protein aggregates in neurodegenerative diseases. Nat Rev Mol Cell Biol. 2010;11(4):301-307.
Halliday GM, Holton JL, Revesz T, et al. Neuropathology underlying clinical variability in patients with synucleinopathies. Acta Neuropathol. 2011;122(2):187-204.
Jellinger KA. Neuropathology of multiple system atrophy: new thoughts about pathogenesis. Mov Disord. 2014;29(14):1720-1741.
Krismer F, Jellinger KA, Scholz SW, et al. Multiple system atrophy as emerging template for accelerated drug discovery in α-synucleinopathies. Parkinsonism Relat Disord. 2014;20(8):793-799.
Kuzdas-Wood D, Stefanova N, Jellinger KA, et al. Towards translational therapies for multiple system atrophy. Prog Neurobiol. 2014;118:19-35.
National Library of Medicine (US). Genetics Home Reference [Internet]. Bethesda (MD): The Library; 2014 Dec 22. Multiple system atrophy; [reviewed 2012 Jan; cited 2014 Dec 27]. Available at: http://ghr.nlm.nih.gov/condition/multiple-system-atrophy.
Nonnekes J, Aerts MB, Abdo WF, Bloem BR. Medio-lateral balance impairment differentiates between Parkinson’s disease and atypical parkinsonism. J Parkinsons Dis. 2014;4(4):567-569.
Reyes JF, Rey NL, Bousset L, et al. Alpha-synuclein transfers from neurons to oligodendrocytes. Glia. 2014;62(3):387-398.
Scholz SW, Houlden H, Schulte C, et al. SNCA variants are associated with increased risk for multiple system atrophy. Ann Neurol. 2009;65(5):610-614.
Sieber BA, Landis S, Koroshetz W, et al. Prioritized research recommendations from the National Institute of Neurological Disorders and Stroke Parkinson's Disease 2014 conference. Ann Neurol. 2014;76(4):469-472.