Publication

Cellular protein quality control and the evolution of aggregates in spinocerebellar ataxia type 3 (SCA3)

Seidel, K., Meister, M., Dugbartey, G. J., Zijlstra, M. P., Vinet, J., Brunt, E. R. P., van Leeuwen, F. W., Rueb, U., Kampinga, H. H. & den Dunnen, W. F. A., Oct-2012, In : Neuropathology and Applied Neurobiology. 38, 6, p. 548-558 11 p.

Research output: Contribution to journalArticleAcademicpeer-review

APA

Seidel, K., Meister, M., Dugbartey, G. J., Zijlstra, M. P., Vinet, J., Brunt, E. R. P., van Leeuwen, F. W., Rueb, U., Kampinga, H. H., & den Dunnen, W. F. A. (2012). Cellular protein quality control and the evolution of aggregates in spinocerebellar ataxia type 3 (SCA3). Neuropathology and Applied Neurobiology, 38(6), 548-558. https://doi.org/10.1111/j.1365-2990.2011.01220.x

Author

Seidel, K. ; Meister, M. ; Dugbartey, G. J. ; Zijlstra, M. P. ; Vinet, J. ; Brunt, E. R. P. ; van Leeuwen, F. W. ; Rueb, U. ; Kampinga, H. H. ; den Dunnen, W. F. A. / Cellular protein quality control and the evolution of aggregates in spinocerebellar ataxia type 3 (SCA3). In: Neuropathology and Applied Neurobiology. 2012 ; Vol. 38, No. 6. pp. 548-558.

Harvard

Seidel, K, Meister, M, Dugbartey, GJ, Zijlstra, MP, Vinet, J, Brunt, ERP, van Leeuwen, FW, Rueb, U, Kampinga, HH & den Dunnen, WFA 2012, 'Cellular protein quality control and the evolution of aggregates in spinocerebellar ataxia type 3 (SCA3)', Neuropathology and Applied Neurobiology, vol. 38, no. 6, pp. 548-558. https://doi.org/10.1111/j.1365-2990.2011.01220.x

Standard

Cellular protein quality control and the evolution of aggregates in spinocerebellar ataxia type 3 (SCA3). / Seidel, K.; Meister, M.; Dugbartey, G. J.; Zijlstra, M. P.; Vinet, J.; Brunt, E. R. P.; van Leeuwen, F. W.; Rueb, U.; Kampinga, H. H.; den Dunnen, W. F. A.

In: Neuropathology and Applied Neurobiology, Vol. 38, No. 6, 10.2012, p. 548-558.

Research output: Contribution to journalArticleAcademicpeer-review

Vancouver

Seidel K, Meister M, Dugbartey GJ, Zijlstra MP, Vinet J, Brunt ERP et al. Cellular protein quality control and the evolution of aggregates in spinocerebellar ataxia type 3 (SCA3). Neuropathology and Applied Neurobiology. 2012 Oct;38(6):548-558. https://doi.org/10.1111/j.1365-2990.2011.01220.x


BibTeX

@article{18fa6c6c0eca4d21abca7e6b33782f5c,
title = "Cellular protein quality control and the evolution of aggregates in spinocerebellar ataxia type 3 (SCA3)",
abstract = "K. Seidel, M. Meister, G. J. Dugbartey, M. P. Zijlstra, J. Vinet, E. R. P. Brunt, F. W. van Leeuwen, U. Rub, H. H. Kampinga and W. F. A. den Dunnen (2012) Neuropathology and Applied Neurobiology38, 548558 Cellular protein quality control and the evolution of aggregates in spinocerebellar ataxia type 3 (SCA3) Aims: A characteristic of polyglutamine diseases is the increased propensity of disease proteins to aggregate, which is thought to be a major contributing factor to the underlying neurodegeneration. Healthy cells contain mechanisms for handling protein damage, the protein quality control, which must be impaired or inefficient to permit proteotoxicity under pathological conditions. Methods: We used a quantitative analysis of immunohistochemistry of the pons of eight patients with the polyglutamine disorder spinocerebellar ataxia type 3. We employed the anti-polyglutamine antibody 1C2, antibodies against p62 that is involved in delivering ubiquitinated protein aggregates to autophagosomes, antibodies against the chaperones HSPA1A and DNAJB1 and the proteasomal stress marker UBB+1. Results: The 1C2 antibody stained neuronal nuclear inclusions (NNIs), diffuse nuclear staining (DNS), granular cytoplasmic staining (GCS) and combinations, with reproducible distribution. P62 always co-localized with 1C2 in NNI. DNS and GCS co-stained with a lower frequency. UBB+1 was present in a subset of neurones with NNI. A subset of UBB+1-containing neurones displayed increased levels of HSPA1A, while DNAJB1 was sequestered into the NNI. Conclusion: Based on our results, we propose a model for the aggregation-associated pathology of spinocerebellar ataxia type 3: GCS and DNS aggregation likely represents early stages of pathology, which progresses towards formation of p62-positive NNI. A fraction of NNI exhibits UBB+1 staining, implying proteasomal overload at a later stage. Subsequently, the stress-inducible HSPA1A is elevated while DNAJB1 is recruited into NNIs. This indicates that the stress response is only induced late when all endogenous protein quality control systems have failed.",
keywords = "DNAJ, HSPA, protein aggregation, protein quality control, spinocerebellar ataxia, DOMINANT CEREBELLAR ATAXIAS, HUNTINGTONS-DISEASE, IN-VIVO, NEURONAL INTRANUCLEAR, MOLECULAR CHAPERONES, MUTANT HUNTINGTIN, UBIQUITIN, DEGRADATION, INCLUSIONS, MACHINERY",
author = "K. Seidel and M. Meister and Dugbartey, {G. J.} and Zijlstra, {M. P.} and J. Vinet and Brunt, {E. R. P.} and {van Leeuwen}, {F. W.} and U. Rueb and Kampinga, {H. H.} and {den Dunnen}, {W. F. A.}",
year = "2012",
month = oct,
doi = "10.1111/j.1365-2990.2011.01220.x",
language = "English",
volume = "38",
pages = "548--558",
journal = "Neuropathology and Applied Neurobiology",
issn = "0305-1846",
publisher = "WILEY-BLACKWELL",
number = "6",

}

RIS

TY - JOUR

T1 - Cellular protein quality control and the evolution of aggregates in spinocerebellar ataxia type 3 (SCA3)

AU - Seidel, K.

AU - Meister, M.

AU - Dugbartey, G. J.

AU - Zijlstra, M. P.

AU - Vinet, J.

AU - Brunt, E. R. P.

AU - van Leeuwen, F. W.

AU - Rueb, U.

AU - Kampinga, H. H.

AU - den Dunnen, W. F. A.

PY - 2012/10

Y1 - 2012/10

N2 - K. Seidel, M. Meister, G. J. Dugbartey, M. P. Zijlstra, J. Vinet, E. R. P. Brunt, F. W. van Leeuwen, U. Rub, H. H. Kampinga and W. F. A. den Dunnen (2012) Neuropathology and Applied Neurobiology38, 548558 Cellular protein quality control and the evolution of aggregates in spinocerebellar ataxia type 3 (SCA3) Aims: A characteristic of polyglutamine diseases is the increased propensity of disease proteins to aggregate, which is thought to be a major contributing factor to the underlying neurodegeneration. Healthy cells contain mechanisms for handling protein damage, the protein quality control, which must be impaired or inefficient to permit proteotoxicity under pathological conditions. Methods: We used a quantitative analysis of immunohistochemistry of the pons of eight patients with the polyglutamine disorder spinocerebellar ataxia type 3. We employed the anti-polyglutamine antibody 1C2, antibodies against p62 that is involved in delivering ubiquitinated protein aggregates to autophagosomes, antibodies against the chaperones HSPA1A and DNAJB1 and the proteasomal stress marker UBB+1. Results: The 1C2 antibody stained neuronal nuclear inclusions (NNIs), diffuse nuclear staining (DNS), granular cytoplasmic staining (GCS) and combinations, with reproducible distribution. P62 always co-localized with 1C2 in NNI. DNS and GCS co-stained with a lower frequency. UBB+1 was present in a subset of neurones with NNI. A subset of UBB+1-containing neurones displayed increased levels of HSPA1A, while DNAJB1 was sequestered into the NNI. Conclusion: Based on our results, we propose a model for the aggregation-associated pathology of spinocerebellar ataxia type 3: GCS and DNS aggregation likely represents early stages of pathology, which progresses towards formation of p62-positive NNI. A fraction of NNI exhibits UBB+1 staining, implying proteasomal overload at a later stage. Subsequently, the stress-inducible HSPA1A is elevated while DNAJB1 is recruited into NNIs. This indicates that the stress response is only induced late when all endogenous protein quality control systems have failed.

AB - K. Seidel, M. Meister, G. J. Dugbartey, M. P. Zijlstra, J. Vinet, E. R. P. Brunt, F. W. van Leeuwen, U. Rub, H. H. Kampinga and W. F. A. den Dunnen (2012) Neuropathology and Applied Neurobiology38, 548558 Cellular protein quality control and the evolution of aggregates in spinocerebellar ataxia type 3 (SCA3) Aims: A characteristic of polyglutamine diseases is the increased propensity of disease proteins to aggregate, which is thought to be a major contributing factor to the underlying neurodegeneration. Healthy cells contain mechanisms for handling protein damage, the protein quality control, which must be impaired or inefficient to permit proteotoxicity under pathological conditions. Methods: We used a quantitative analysis of immunohistochemistry of the pons of eight patients with the polyglutamine disorder spinocerebellar ataxia type 3. We employed the anti-polyglutamine antibody 1C2, antibodies against p62 that is involved in delivering ubiquitinated protein aggregates to autophagosomes, antibodies against the chaperones HSPA1A and DNAJB1 and the proteasomal stress marker UBB+1. Results: The 1C2 antibody stained neuronal nuclear inclusions (NNIs), diffuse nuclear staining (DNS), granular cytoplasmic staining (GCS) and combinations, with reproducible distribution. P62 always co-localized with 1C2 in NNI. DNS and GCS co-stained with a lower frequency. UBB+1 was present in a subset of neurones with NNI. A subset of UBB+1-containing neurones displayed increased levels of HSPA1A, while DNAJB1 was sequestered into the NNI. Conclusion: Based on our results, we propose a model for the aggregation-associated pathology of spinocerebellar ataxia type 3: GCS and DNS aggregation likely represents early stages of pathology, which progresses towards formation of p62-positive NNI. A fraction of NNI exhibits UBB+1 staining, implying proteasomal overload at a later stage. Subsequently, the stress-inducible HSPA1A is elevated while DNAJB1 is recruited into NNIs. This indicates that the stress response is only induced late when all endogenous protein quality control systems have failed.

KW - DNAJ

KW - HSPA

KW - protein aggregation

KW - protein quality control

KW - spinocerebellar ataxia

KW - DOMINANT CEREBELLAR ATAXIAS

KW - HUNTINGTONS-DISEASE

KW - IN-VIVO

KW - NEURONAL INTRANUCLEAR

KW - MOLECULAR CHAPERONES

KW - MUTANT HUNTINGTIN

KW - UBIQUITIN

KW - DEGRADATION

KW - INCLUSIONS

KW - MACHINERY

U2 - 10.1111/j.1365-2990.2011.01220.x

DO - 10.1111/j.1365-2990.2011.01220.x

M3 - Article

C2 - 21916928

VL - 38

SP - 548

EP - 558

JO - Neuropathology and Applied Neurobiology

JF - Neuropathology and Applied Neurobiology

SN - 0305-1846

IS - 6

ER -

ID: 5671143