Polyglutamine aggregation in H untington's disease and spinocerebellar ataxia type 3: similar mechanisms in aggregate formation

• Published in: Neuropathology and applied neurobiology Vol. 42; no. 2; pp. 153 - 166
• Main Authors: Seidel, K., Siswanto, S., Fredrich, M., Bouzrou, M., Brunt, E. R., van Leeuwen, F. W., Kampinga, H. H., Korf, H. ‐W., Rüb, U., den Dunnen, W. F. A.
• Format: Journal Article
• Language: English
• Published: 01-02-2016
• ISSN: 0305-1846; 1365-2990
• DOI: 10.1111/nan.12253

Aims
Polyglutamine (
polyQ
) diseases are characterized by the expansion of a polymorphic glutamine sequence in disease‐specific proteins and exhibit aggregation of these proteins. This is combated by the cellular protein quality control (
PQC
) system, consisting of chaperone‐mediated refolding as well as proteasomal and lysosomal degradation pathways. Our recent study in the
polyQ
disease spinocerebellar ataxia type 3 (
SCA3
) suggested a distinct pattern of protein aggregation and
PQC
dysregulation.
Methods
To corroborate these findings we have investigated immunohistochemically stained 5 μm sections from different brain areas of
H
untington's disease (
HD
) and
SCA3
patients.
Results
Irrespective of disease and brain region, we observed peri‐ and intranuclear
polyQ
protein aggregates. A subset of neurones with intranuclear inclusions bodies exhibited signs of proteasomal dysfunction, up‐regulation of
HSPA1A
and re‐distribution of
DNAJB1
. The extent of the observed effects varied depending on brain area and disease protein.
Conclusions
Our results suggest a common sequence, in which formation of cytoplasmic and nuclear inclusions precede proteasomal impairment and induction of the cellular stress response. Clearly, impairment of the
PQC
is not the primary cause for inclusion formation, but rather a consequence that might contribute to neuronal dysfunction and death. Notably, the inclusion pathology is not directly correlated to the severity of the degeneration in different areas, implying that different populations of neurones respond to
polyQ
aggregation with varying efficacy and that protein aggregation outside the neuronal perikaryon (e.g. axonal aggregates) or other effects of
polyQ
aggregation, which are more difficult to visualize, may contribute to neurodegeneration.