Expression pattern of apoptosis-related markers in Huntington's disease

• Published in: Acta neuropathologica 2005-04, Vol.109 (3), p.321-328
• Main Authors: Vis, José C, Schipper, Ellis, de Boer-van Huizen, Roelie T, Verbeek, Marcel M, de Waal, Rob M W, Wesseling, Pieter, ten Donkelaar, Hans J, Kremer, Berry
• Format: Article
• Language: English
• Subjects: Adult; Aged; Aged, 80 and over; Apoptosis - physiology; bcl-2-Associated X Protein; Biomarkers - metabolism; Caspase 3; Caspases - metabolism; Collagen Type XI - metabolism; Female; Gene Expression Regulation - physiology; Glial Fibrillary Acidic Protein - metabolism; Humans; Huntington Disease - metabolism; Huntington Disease - pathology; Immunohistochemistry - methods; In Situ Nick-End Labeling - methods; Male; Middle Aged; Models, Biological; Neuroglia - metabolism; Neuroglia - pathology; Neurons - metabolism; Neurons - pathology; Poly (ADP-Ribose) Polymerase-1; Poly(ADP-ribose) Polymerases; Postmortem Changes; Proto-Oncogene Proteins c-bcl-2 - metabolism
• ISSN: 0001-6322; 1432-0533
• DOI: 10.1007/s00401-004-0957-5

Inappropriate apoptosis has been implicated in the mechanism of neuronal death in Huntington's disease (HD). In this study, we report the expression of apoptotic markers in HD caudate nucleus (grades 1-4) and compare this with controls without neurological disease. Terminal transferase-mediated biotinylated-UTP nick end-labeling (TUNEL)-positive cells were detected in both control and HD brains. However, typical apoptotic cells were present only in HD, especially in grade 3 and 4 specimens. Expression of the pro-apoptotic protein Bax was increased in HD brains compared to controls, demonstrating a cytoplasmic expression pattern in predominantly shrunken and dark neurons, which were most frequently seen in grades 2 and 3. Control brains displayed weak perinuclear expression of the anti-apoptotic protein Bcl-2, whereas in HD brains Bcl-2 immunoreactivity was markedly enhanced, especially in severely affected grade 4 brains, and was observed in both healthy neurons and dark neurons. Caspase-3, an executioner protease, was only found in four HD brains of different grades and was not expressed in controls. A strong neuronal and glial expression of poly(ADP-ribose) polymerase (PARP)-immunoreactivity was observed in HD brains. These data strongly suggest the involvement of apoptosis in HD. The exact apoptotic pathway occurring in HD neurodegeneration remains yet unclear. However, the presence of late apoptotic events, such as enhanced PARP expression and many TUNEL-positive cells accompanied with weak caspase-3 immunoreactivity in severely affected HD brains, suggests that caspase-mediated neuronal death only plays a minor role in HD.