Figure 2.

Model for cellular pathogenesis in Huntington's disease. The molecular chaperones Hsp70 and Hsp40 promote the folding of newly synthesized huntingtin (htt) into a native structure. Wild-type htt is predominantly cytoplasmic and probably functions in vesicle transport, cytoskeletal anchoring, clathrin-mediated endocytosis, neuronal transport or postsynaptic signalling. htt may be transported into the nucleus and have a role in transcriptional regulation (1). Chaperones can facilitate the recognition of abnormal proteins, promoting either their refolding, or ubiquitination (Ub) and subsequent degradation by the 26S proteasome. The HD mutation induces conformational changes and is likely to cause the abnormal folding of htt, which, if not corrected by chaperones, leads to the accumulation of misfolded htt in the cytoplasm (2). Alternatively, mutant htt might also be proteolytically cleaved, giving rise to amino-terminal fragments that form β-sheet structures (3). Ultimately, toxicity might be elicited by mutant full-length htt or by cleaved N-terminal fragments, which may form soluble monomers, oligomers or large insoluble aggregates. In the cytoplasm, mutant forms of htt may impair the ubiquitin–proteasome system (UPS), leading to the accumulation of more proteins that are misfolded (4). These toxic proteins might also impair normal vesicle transport and clathrin-mediated endocytosis. Also, the presence of mutant htt could activate proapoptotic proteins directly or indirectly by mitochondrial damage, leading to greater cellular toxicity and other deleterious effects (5). In an effort to protect itself, the cell accumulates toxic fragments into ubiquitinated cytoplasmic perinuclear aggregates (6). In addition, mutant htt can be translocated into the nucleus to form nuclear inclusions, which may disrupt transcription and the UPS (7).