Models of pathogenesis

A number o f theories have been proposed for the pathogenic action o f the expanded glutamine repeats. The majority o f these models have been investigated with HD but one of these models could explain the pathology underlying schizophrenia or any o f the other neurological disorders associated with TNR expansion. The proposed models are described below (see reviews by Nasir et al., 1996; Housman, 1995).

(i) A modification o f the structure/function o f the protein could cause abnormal interaction with other proteins, for instance other glutamine containing proteins (Perutz et al., 1994). The authors showed by molecular modelling followed by optical, electron and X-ray diffraction studies that synthetic poly-L-glutamine forms p-sheets, strongly held together by hydrogen bonds. The glutamine stretch is capable o f linking p-strands

Introduction together into sheets or barrels by networks o f hydrogen bonds between their main-chain amides and between their polar side chains. The authors referred to the glutamine stretch as ‘polar zippers’. Based on these observations the following mechanisms o f pathogenesis were proposed. Firstly, glutamine repeats that are involved in the joining o f specific complementary proteins as part o f normal transcription regulation acquire excessively high affinities for each other. On the other hand, they could acquire non­ specific affinities for other regulatory proteins when they become too long, thereby causing disease. In either case, the conjugate itself might be directly neuronopathic, or the process o f conjugation might deplete the level o f unbound protein X below a limit that is necessary for the normal life span o f selected motor neurones (Esfarjani et a l, 1995). Secondly, extension o f the glutamine repeats may cause the affected proteins to agglomerate and precipitate in neurones. Symptoms may set in when these precipitates have reached a critical size or have resulted in a critical number o f neural blocks. This could explain why symptoms appear earlier in life and become more severe the larger the extension o f the glutamine repeats and why the main histological manifestations o f HD consist o f neural degeneration. However, immunostaining o f Purkinje cells and cells in the human frontal cereberal cortex with an antibody against the HD protein showed no difference between cells fi*om a normal individual and those from a HD patient (reviewed by Perutz et a l, 1994).

(ii) The polyglutamine expanded proteins may become conjugated to other proteins by the action o f neuronal transglutaminase-catalysed isopeptide crosslinks (reviewed by Trottier et a l, 1995b; Esfarjani et a l, 1995).

(iii) Several proteins have been shown to bind to expanded glutamine repeats and could be relevant to the pathogenesis o f the disorders. Li et al. (1995) identified a novel huntingtin-associated protein (HAP-1) with an unknown function. HAP-1 has been observed to be selectively expressed in brain in areas such as the caudate and cortex, that are most affected in HD, in contrast to the ubiquitous expression o f the HD gene. This pattern suggests that HAP-1 may contribute to the brain-specific pathology o f HD. The association between HAP-1 and huntingtin has also been shown to be enhanced by increasing lengths o f glutamine repeats. It has been suggested that this enhanced binding may be influenced by adjacent amino acids (as there is no binding to the atropin-1 protein which contains essentially the same number o f glutamines as the HD constructs) or on

Introduction the other hand by a conformational change induced by the expanded glutamine.

Glyceraldehyde-3-phosphate dehydrogenase (GAPDH is a common multifunctional enzyme involved in energy metabolism. It is essential in glycolysis and is also a uracil DNA glycosylase) has been reported to bind to the normal protein products o f HD, DRPLA and SCAl (Burke et al., 1996). Differences in the binding o f mutant and native proteins with GAPDH may affect the enzymatic functions o f GAPDH. GAPDH is ubiquitously expressed and is co-localised in the cells that express the HD, DRPLA and SCAl proteins, making interactions possible. McLaughlin et a l (1996) identified RNA- binding proteins that interact with trinucleotide GAG repeats in a tissue-specific and GAG length-dependent manner. The authors hypothesised that an altered mRNA- protein interaction may contribute to the pathology o f these diseases.

(v) Goldberg et al. (1996) showed that apopain (an enzyme responsible for apoptosis in mammalian cells) specifically cleaves huntingtin. Furthermore, the authors have shown that the longer the polyglutamine tract (in the range associated with the clinical presentation o f HD), the more susceptible huntingtin is to apopain cleavage. The results have suggested that the underlying pathogenesis o f HD may involve inappropriate apoptosis. Cleavage o f huntingtin could either generate toxic breakdown products and/or inactivate the putative anti-apoptotic function o f huntingtin. This suggests that huntingtin in its intact form could normally play an important role in cell survival and prevention o f apoptosis. Furthermore, increased cleavage activity by apopain associated with an expanded polyglutamine stretch is consistent with earlier AAO seen in juvenile HD.

Although these diseases share a common genetic mechanism o f expanded GAG repeats, each disorder is associated with a unique gene and has a specific pattern o f degeneration and clinical phenotype. It has been hypothesised that selective neuronal degeneration cannot be explained by the cellular distribution o f these proteins since both the normal and mutant proteins in these diseases are widely expressed throughout the GNS. It has also been proposed that other factors such as alternative splicing, post-translational modification and the presence o f other cell-specific protein interactions may play a role in the pathogenesis.

Introduction