Changed distribution pattern of the constitutive rather than the inducible HSP70 chaperone in neuromelanin-containing neurones of the Parkinsonian midbrain.
Aberrant protein aggregation has been recognized as an important factor in the degeneration of melanized dopaminergic neurones in Parkinson's disease (PD). The constitutive (HSP73) and (heat)-inducible (HSP72) proteins of the heat shock 70 family form a major defence system against pathological protein aggregation. However, the distribution patterns of these chaperones in nigral neuromelanin-laden neurones are largely unknown. The present study determined the distribution of HSP72 and HSP73 in control and Parkinsonian substantia nigra, using immunohistochemistry. In the neuromelanin-laden neurones of controls, HSP72 was nondetectable, whereas HSP73 was weakly expressed in both the cytosol and the nucleus. Surprisingly, in PD subjects, marked nuclear HSP73, but not HSP72 immunoreactivity was observed, while cytosolic immunoreactivity of the two chaperones resembled the labelling pattern observed in controls. Furthermore, HSP73 immunoreactivity was observed in a subset of the Lewy bodies (LBs) detected in the substantia nigra of PD subjects, whereas only few of these LBs were labelled with HSP72. Interestingly, HSP72 and to a lesser extent HSP73 immunoreactivity was much stronger in nonmelanized neurones as compared with melanized neurones in this area. Thus, we conclude that the distribution pattern of HSP73 rather than HSP72 is changed in the nigral neuromelanin-laden neurones of PD subjects as compared with control subjects. The impaired ability of aged, dopaminergic neurones to express high levels of chaperones, may contribute to the preferential vulnerability of the latter cells in PD.
Andringa
G
G
Department of Medical Pharmacology, VU University Medical Center, Institute for Clinical and Experimental Neurosciences, ICEN, Van der Boechorststraat 7, 1081 BT Amsterdam, the Netherlands. G.andringa@vumc.nl
Bol
J G J M
JG
Wang
X
X
Boekel
A
A
Bennett
M C
MC
Chase
T N
TN
Drukarch
B
B
D000368:Aged; D015153:Blotting, Western; D005260:Female; D018840:HSP70 Heat-Shock Proteins / Q000378:metabolism*; D006801:Humans; D007091:Image Processing, Computer-Assisted; D007150:Immunohistochemistry; D016631:Lewy Bodies / Q000378:metabolism / Q000473:pathology; D008297:Male; D008543:Melanins / Q000378:metabolism*; D008636:Mesencephalon / Q000378:metabolism* / Q000473:pathology; D008875:Middle Aged; D009474:Neurons / Q000378:metabolism* / Q000473:pathology; D010300:Parkinson Disease / Q000378:metabolism* / Q000473:pathology
D018840:HSP70 Heat-Shock Proteins; D008543:Melanins; C014121:neuromelanin