Mouse Studies Show That E6-ap Is Strongly Implicated In The Aetiology Of

Mouse studies show that E6-AP is strongly implicated in the aetiology of Anglemann's syndrome. The defective gene is localised to 15q11-q13. Experimental and post-mortem studies show abnormalities in the Purkinje cells and the hippocampal neurones in every case (Albrecht et al. 1997).
The accumulation of ubiquitin conjugates and / or inclusion bodies have been found in a broad spectrum of neuro-degenerative diseases. Some will produce characteristic appearances under the electron microscope. The Lewy bodies in the brain stem being the hallmark of Parkinson's disease, the neurofibrillary tangles of Alzheimer's disease, nuclear inclusions in the polyglutamine extension disorders such as Huntingdon's Chorea and Kennedy's syndrome together with spinocerebellar ataxia. Bunina bodies are described in Amyotrophic lateral sclerosis

In all these cases, the ubiquitin-proteasome system is strongly suspected but not yet definitely implicated. One of the reasons for this is the fact that both Alzheimer's disease and Parkinson's disease are not well defined, discrete clinical entities, but clinical syndromes with different aetiologies. Parkinson's disease is the most common of all of the neuro-degenerative movement diseases. It is characterised, on a micro-anatomical level, by a progressive and extensive loss of the dopaminergic neurones in the substantia nigra pars compacta. (Eriksen et al. 2005)
It could be that the discovery of the Lewy inclusion bodies or the neurofibrillary tangles, which are known to be the physical manifestation of ubiquitin-proteasome system conjugates, may actually be only secondary to the basic pathology and reflect the unsuccessful attempts by the ubiquitin-proteasome system to eliminate damaged, modified or abnormal proteins.
The initial hypothesis described these accumulations as the natural tendency of abnormal proteins to accumulate and aggregate (Johnston et al. 2000) but more recent work suggests that this may be a naive view and the whole process may be far more complex involving a number of different intra-cellular mechanisms (Fabunmi et al. 2000) - one of which may be the actual inhibition of the ubiquitin-proteasome system by the accumulated proteins themselves (Bence et al. 2001).

Whatever the actual mechanism, it would appear that the aggregation or clumping of these abnormal proteins is a common factor in many of the hereditary neuro-degenerative diseases particularly the sporadic varieties.
In Parkinson's disease the situation appears to be particularly complex as far as the ubiquitin-proteasome system is concerned. Mutations in A53T (alpha-synuclein) have been positively identified as being implicated in the autosomal dominant forms of Parkinson's disease.