Lee JG, Takahama S, Zhang G, Tomarev SI, Ye Y.
Unconventional secretion of misfolded proteins promotes adaptation to proteasome dysfunction in mammalian cells.
Nat Cell Biol. 2016 Jun 13;
PubMed.
Cellular homeostasis is essential for cells, in particular neurons, to assure proper network function.
In addition to well-defined cellular safeguards such as ERAD, the ubiquitin-proteasome system (UPS), and autophagy, now a new UPS pathway with USP-19 as a pivotal regulator has been added for short-term protection of cells.
This impressive paper presents a lot of evidence for MAPS excluding alternative explanations such as autophagosomes and exosomes. Indeed when the UPS stops delivering, the MAPS pathway, already at the level of the endoplasmic reticulum, is very useful.
Of course follow-up questions can be raised, such as what is the predictive value for the in-vivo situation? This point was raised by Schipanski et al., 2014, where a mouse model for a serpinopathy called FENIB, aka familial encephalopathy with inclusion bodies, was crossbred with a mouse model with a flawed UPS that is obtainable via Jackson labs, JAX 008833, line #3413.
In fact, this very paper by Lee et al. opens new avenues for research toward specific therapies for conformational diseases such as tauopathies and many polyglutamine diseases.
References:
Schipanski A, Oberhauser F, Neumann M, Lange S, Szalay B, Krasemann S, van Leeuwen FW, Galliciotti G, Glatzel M.
Lectin OS-9 delivers mutant neuroserpin to endoplasmic reticulum associated degradation in familial encephalopathy with neuroserpin inclusion bodies.
Neurobiol Aging. 2014 Oct;35(10):2394-403. Epub 2014 Apr 8
PubMed.
Beginning in the 1980s, experiments have shown that prions injected into the eye translocate with high spatial and temporal specificity to downstream components of the visual system (Buyukmihci et al., 1983; Fraser, 1982; Kimberlin et al., 1986; Liberski et al., 2012; Liberski et al., 1990; Scott et al., 1992). The most parsimonious explanation for this systematic pattern of regional involvement is that the prions spread by axonal transport and cell-to-cell transfer. Recent studies have found that other neurodegeneration-associated misfolded proteins, including α-synuclein, tau, and Aβ, also appear to spread through the connectome. All evidence points to prion-like seeds as the pathogenic agents, but how they translocate has been uncertain.
In a recent review, Walsh and Selkoe challenged the research community to clarify the cellular mechanisms that underlie the spread of misfolded proteins within the brain (Walsh and Selkoe, 2016; Apr 2016 webinar). By identifying a previously unknown process by which cells secrete misfolded cytosolic proteins into the extracellular space, Lee and colleagues have taken a compelling step toward meeting this challenge.
Moreover, in pinpointing USP19 as a key chaperone for the secretion of certain misfolded proteins, the findings add a new pathway to the list of potential therapeutic targets for neurodegenerative disease. The study reaffirms that cells can respond to adversity in unexpected ways, and so it seems likely that more unconventional proteostatic pathways await discovery.
Some other issues are raised by the discovery of misfolding-associated protein secretion (MAPS). Misfolded proteins are favored by the unconventional secretion pathway when proteasomes become incapable of efficient degradation. Proteasomal function decreases with age (Saez and Vilchez, 2014), particularly in postmitotic cells (Keller et al., 2002); the predicted increase in MAPS could explain why advancing age is a risk factor for synucleinopathy.
It would be useful to know if secreted seeds normally are taken up and degraded by local glial cells, and, if so, whether this process declines with age or under conditions of cellular stress. From the standpoint of organismic survival, it seems counterproductive for cells to share proteopathic seeds with other cells. However, by temporarily lowering the local intracellular concentration of misfolded proteins, MAPS may at least delay cell death and brain dysfunction. The transition from proteasomal degradation to MAPS might leave biochemical signatures that could serve as biomarkers during the long, clinically silent period that precedes obvious signs and symptoms of disease.
References:
Buyukmihci N, Goehring-Harmon F, Marsh RF.
Neural pathogenesis of experimental scrapie after intraocular inoculation of hamsters.
Exp Neurol. 1983 Aug;81(2):396-406.
PubMed.
Fraser H.
Neuronal spread of scrapie agent and targeting of lesions within the retino-tectal pathway.
Nature. 1982 Jan 14;295(5845):149-50.
PubMed.
Kimberlin RH, Walker CA.
Pathogenesis of scrapie (strain 263K) in hamsters infected intracerebrally, intraperitoneally or intraocularly.
J Gen Virol. 1986 Feb;67 ( Pt 2):255-63.
PubMed.
Liberski PP, Hainfellner JA, Sikorska B, Budka H.
Prion protein (PrP) deposits in the tectum of experimental Gerstmann-Sträussler-Scheinker disease following intraocular inoculation.
Folia Neuropathol. 2012;50(1):85-8.
PubMed.
Liberski PP, Yanagihara R, Gibbs CJ Jr, Gajdusek DC.
Spread of Creutzfeldt-Jakob disease virus along visual pathways after intraocular inoculation.
Arch Virol. 1990;111(1-2):141-7.
PubMed.
Scott JR, Davies D, Fraser H.
Scrapie in the central nervous system: neuroanatomical spread of infection and Sinc control of pathogenesis.
J Gen Virol. 1992 Jul;73 ( Pt 7):1637-44.
PubMed.
Walsh DM, Selkoe DJ.
A critical appraisal of the pathogenic protein spread hypothesis of neurodegeneration.
Nat Rev Neurosci. 2016 Apr;17(4):251-60.
PubMed.
Saez I, Vilchez D.
The Mechanistic Links Between Proteasome Activity, Aging and Age-related Diseases.
Curr Genomics. 2014 Feb;15(1):38-51.
PubMed.
Keller JN, Gee J, Ding Q.
The proteasome in brain aging.
Ageing Res Rev. 2002 Apr;1(2):279-93.
PubMed.
The investigators have identified a novel pathway that is active during secretion of misfolded α-synuclein to the extracellular space. These are very exciting findings that potentially will impact research into novel therapeutic targets for Parkinson¹s disease and related α-synucleinopathies. The concept that α-synuclein can act in a prion-like fashion in Parkinson¹s disease has gained widespread acceptance, but it has remained controversial how, and when, misfolded α-synuclein is secreted from neurons. While the authors have mostly focused their studies on non-neuronal cells, the findings are very important and provide insight into a key molecular mechanism of high relevance to Parkinson's pathogenesis.
The study by Lee et al. has uncovered a new coping mechanism when cells are faced with impaired proteasome degradation and subsequent overload of aberrant proteins. This pathway is distinct from the exosome pathway, whereby misfolded proteins are selectively secreted through ER-associated late endosomes.
The study is to be complimented for its significance and quality results, but it remains to be seen if this mechanism is present in cultured primary neurons or in vivo, and under normal expression of USP19. In that regard, the authors provide physiological relevance by showing that overexpression of USP19 promotes α-synuclein but not tau secretion, although both proteins are known to have unfolding and cell-to-cell propagation properties. Further research in relevant transgenic mouse models can help elucidate the therapeutic implication of this pathway in inhibiting the spreading pathology in neurodegenerative diseases.
Comments
University Maastricht
Cellular homeostasis is essential for cells, in particular neurons, to assure proper network function.
In addition to well-defined cellular safeguards such as ERAD, the ubiquitin-proteasome system (UPS), and autophagy, now a new UPS pathway with USP-19 as a pivotal regulator has been added for short-term protection of cells.
This impressive paper presents a lot of evidence for MAPS excluding alternative explanations such as autophagosomes and exosomes. Indeed when the UPS stops delivering, the MAPS pathway, already at the level of the endoplasmic reticulum, is very useful.
Of course follow-up questions can be raised, such as what is the predictive value for the in-vivo situation? This point was raised by Schipanski et al., 2014, where a mouse model for a serpinopathy called FENIB, aka familial encephalopathy with inclusion bodies, was crossbred with a mouse model with a flawed UPS that is obtainable via Jackson labs, JAX 008833, line #3413.
In fact, this very paper by Lee et al. opens new avenues for research toward specific therapies for conformational diseases such as tauopathies and many polyglutamine diseases.
References:
Schipanski A, Oberhauser F, Neumann M, Lange S, Szalay B, Krasemann S, van Leeuwen FW, Galliciotti G, Glatzel M. Lectin OS-9 delivers mutant neuroserpin to endoplasmic reticulum associated degradation in familial encephalopathy with neuroserpin inclusion bodies. Neurobiol Aging. 2014 Oct;35(10):2394-403. Epub 2014 Apr 8 PubMed.
View all comments by Fred van LeeuwenEmory University
Beginning in the 1980s, experiments have shown that prions injected into the eye translocate with high spatial and temporal specificity to downstream components of the visual system (Buyukmihci et al., 1983; Fraser, 1982; Kimberlin et al., 1986; Liberski et al., 2012; Liberski et al., 1990; Scott et al., 1992). The most parsimonious explanation for this systematic pattern of regional involvement is that the prions spread by axonal transport and cell-to-cell transfer. Recent studies have found that other neurodegeneration-associated misfolded proteins, including α-synuclein, tau, and Aβ, also appear to spread through the connectome. All evidence points to prion-like seeds as the pathogenic agents, but how they translocate has been uncertain.
In a recent review, Walsh and Selkoe challenged the research community to clarify the cellular mechanisms that underlie the spread of misfolded proteins within the brain (Walsh and Selkoe, 2016; Apr 2016 webinar). By identifying a previously unknown process by which cells secrete misfolded cytosolic proteins into the extracellular space, Lee and colleagues have taken a compelling step toward meeting this challenge.
Moreover, in pinpointing USP19 as a key chaperone for the secretion of certain misfolded proteins, the findings add a new pathway to the list of potential therapeutic targets for neurodegenerative disease. The study reaffirms that cells can respond to adversity in unexpected ways, and so it seems likely that more unconventional proteostatic pathways await discovery.
Some other issues are raised by the discovery of misfolding-associated protein secretion (MAPS). Misfolded proteins are favored by the unconventional secretion pathway when proteasomes become incapable of efficient degradation. Proteasomal function decreases with age (Saez and Vilchez, 2014), particularly in postmitotic cells (Keller et al., 2002); the predicted increase in MAPS could explain why advancing age is a risk factor for synucleinopathy.
It would be useful to know if secreted seeds normally are taken up and degraded by local glial cells, and, if so, whether this process declines with age or under conditions of cellular stress. From the standpoint of organismic survival, it seems counterproductive for cells to share proteopathic seeds with other cells. However, by temporarily lowering the local intracellular concentration of misfolded proteins, MAPS may at least delay cell death and brain dysfunction. The transition from proteasomal degradation to MAPS might leave biochemical signatures that could serve as biomarkers during the long, clinically silent period that precedes obvious signs and symptoms of disease.
References:
Buyukmihci N, Goehring-Harmon F, Marsh RF. Neural pathogenesis of experimental scrapie after intraocular inoculation of hamsters. Exp Neurol. 1983 Aug;81(2):396-406. PubMed.
Fraser H. Neuronal spread of scrapie agent and targeting of lesions within the retino-tectal pathway. Nature. 1982 Jan 14;295(5845):149-50. PubMed.
Kimberlin RH, Walker CA. Pathogenesis of scrapie (strain 263K) in hamsters infected intracerebrally, intraperitoneally or intraocularly. J Gen Virol. 1986 Feb;67 ( Pt 2):255-63. PubMed.
Liberski PP, Hainfellner JA, Sikorska B, Budka H. Prion protein (PrP) deposits in the tectum of experimental Gerstmann-Sträussler-Scheinker disease following intraocular inoculation. Folia Neuropathol. 2012;50(1):85-8. PubMed.
Liberski PP, Yanagihara R, Gibbs CJ Jr, Gajdusek DC. Spread of Creutzfeldt-Jakob disease virus along visual pathways after intraocular inoculation. Arch Virol. 1990;111(1-2):141-7. PubMed.
Scott JR, Davies D, Fraser H. Scrapie in the central nervous system: neuroanatomical spread of infection and Sinc control of pathogenesis. J Gen Virol. 1992 Jul;73 ( Pt 7):1637-44. PubMed.
Walsh DM, Selkoe DJ. A critical appraisal of the pathogenic protein spread hypothesis of neurodegeneration. Nat Rev Neurosci. 2016 Apr;17(4):251-60. PubMed.
Saez I, Vilchez D. The Mechanistic Links Between Proteasome Activity, Aging and Age-related Diseases. Curr Genomics. 2014 Feb;15(1):38-51. PubMed.
Keller JN, Gee J, Ding Q. The proteasome in brain aging. Ageing Res Rev. 2002 Apr;1(2):279-93. PubMed.
View all comments by Lary WalkerAssociate Director of the Van Andel Research Institute, and Director of the Center for Neurodegenerative Science
The investigators have identified a novel pathway that is active during secretion of misfolded α-synuclein to the extracellular space. These are very exciting findings that potentially will impact research into novel therapeutic targets for Parkinson¹s disease and related α-synucleinopathies. The concept that α-synuclein can act in a prion-like fashion in Parkinson¹s disease has gained widespread acceptance, but it has remained controversial how, and when, misfolded α-synuclein is secreted from neurons. While the authors have mostly focused their studies on non-neuronal cells, the findings are very important and provide insight into a key molecular mechanism of high relevance to Parkinson's pathogenesis.
View all comments by Patrik BrundinColumbia University
The study by Lee et al. has uncovered a new coping mechanism when cells are faced with impaired proteasome degradation and subsequent overload of aberrant proteins. This pathway is distinct from the exosome pathway, whereby misfolded proteins are selectively secreted through ER-associated late endosomes.
The study is to be complimented for its significance and quality results, but it remains to be seen if this mechanism is present in cultured primary neurons or in vivo, and under normal expression of USP19. In that regard, the authors provide physiological relevance by showing that overexpression of USP19 promotes α-synuclein but not tau secretion, although both proteins are known to have unfolding and cell-to-cell propagation properties. Further research in relevant transgenic mouse models can help elucidate the therapeutic implication of this pathway in inhibiting the spreading pathology in neurodegenerative diseases.
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