Parkinson sporadic

Emerging evidence suggests that dysfunction of the ubiquitin-proteasome system may be part of the pathophysiology of sporadic Parkinson s disease, especially... 

As the ubiquitin proteasome pathway is a main route for protein clearance it is not surprising that in protein-opathies (disease caused by aggregate prone proteins) like sporadic Parkinson- or Huntington disease proteasome activity is reduced. Autosomal recessive loss of function of the E3 ligase parkin is the molecular base for one of the most common forms of familial Parkinson disease. 

Baba M, Nakajo S, Tu PH, Tomita T, Nakaya K, Lee VM, Trojanowski JQ, Iwatsubo T. Aggregation of alpha-synuclein in Lewy bodies of sporadic Parkinson s disease and dementia with Lewy bodies. Am J Pathol 1998 152 879-884. 

Braak H., Tredici K., Rub U. et al. (2003). Staging of brain pathology related to sporadic Parkinson s disease. Neurobiol. Aging 24, 197-211. 

Huang, X., Chen, P. C. and Poole, C. APOE-epsilon2 allele associated with higher prevalence of sporadic Parkinson disease. Neurology 62 2198-2202, 2004. 

On the one hand, the biochemical study of the neuro-pathological lesions led to the identification of their main molecular components. On the other hand, the study of rare, familial forms of Alzheimer s disease, frontotemporal dementia and Parkinson s disease led to the identification of gene defects that cause inherited variants of the different diseases. Remarkably, in these cases, the defective genes have been found to encode or increase the expression of the main components of the neuropathological lesions. It has therefore been established that the basis of the familial forms of these diseases is a toxic property conferred by mutations in the proteins that make up the filamentous lesions. A corollary of this insight is that a similar toxic property may also underlie the much more common, sporadic forms of the diseases. 

Lewy bodies, neurofibrillary lesions and Pick bodies are intracellular filamentous inclusions. It is now well established that Lewy bodies are made of the protein a-synuclein and both neurofibrillary lesions and Pick bodies of the microtubule-associated protein tau. Mutations in the a-synuclein gene or an increase in its copy number cause autosomal-dominantly inherited forms of Parkinson s disease and dementia with Lewy bodies. Mutations in the tau gene cause a familial form of frontotemporal dementia. Here we review the evidence implicating a-synuclein and tau in these inherited and a number of sporadic neurodegenerative diseases. Collectively, a-synucleinopathies and tauopathies account for the vast majority of cases of late-onset neurodegenerative disease (Tables 45-1 and 45-2). 

Lewy body filaments are made of a-synuclein. Shortly after the identification of the genetic defect responsible for Parkinson s disease in the Contursi kindred, Lewy bodies and Lewy neurites in the substantia nigra from patients with sporadic Parkinson s disease were shown to be strongly immunoreactive for a-synuclein [7] (Fig. 45-3). Subsequently, Lewy body filaments were found to be... 

Frontotemporal dementias occur as familial forms and, more commonly, as sporadic diseases. They are characterized by a remarkably circumscribed atrophy of the frontal and temporal lobes of the cerebral cortex, often with additional, subcortical changes. In 1994, an autosomal-dominantly inherited form of frontotemporal dementia with parkinsonism was linked to chromosome 17q21.2. Subsequently, other forms of frontotemporal dementia were linked to this region, resulting in the denomination frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17) for this class of disease. All cases of FTDP-17 have so far shown a filamentous pathology made of hyperphosphorylated tau protein (Fig. 45-7). In 1998, mutations in tau were reported in FTDP-17 patients [29-31]. Since then, more than 30 different mutations have been described in over 80 families with FTDP-17 (Fig. 45-6). 

Satoh J, Kuroda Y. Association of codon 167 Ser/Asn heterozygosity in the Parkin gene with sporadic Parkinson s disease. Neuroreport 1999 10 2735-2739. 

Dujardin K, Defebvre L, Grunberg C (2001) Memory and executive ftmction in sporadic and familial Parkinson s disease. Brain 124 389-398... 

Choi J, Sullards MC, Olzmann JA, Rees HD, Weintraub ST, BostwickDE, Gearing M, Levey Al, Chin LS, Li L (2006) Oxidative damage of DJ-1 is linked to sporadic Parkinson and Alzheimer diseases. J Biol Chem 281 10816-10824... 

Tan EK, Shen H, Tan JM, Lim KL, Fook-Chong S, Hu WP, Paterson MC, Chandran VR, Yew K, Tan C, Yuen Y, Pavanni R, Wong MC, Puvan K, Zhao Y (2005b) Differential expression of splice variant and wild-type parkin in sporadic Parkinson s disease. Neurogenetics 6 179-184 Tan EK, Skipper LM (2007) Pathogenic mutations in Parkinson disease. Hum Mutat 28 641-653... 

Walter J, Kaether C, Steiner H, Haass C (2001) The ceU biology of Alzheimer s disease uncovering the secrets of secretases. Curr Opin Neurobiol 11 585-590 Wang C, Tan JM, Ho MW, Zaiden N, Wong SH, Chew CL, Eng PW, Lim TM, Dawson TM, Lim KL (2005) Alterations in the solubility and intracellular localization of parkin by several familial Parkinson s disease-hnked point mutations. J Neurochem 93 422-431 Waragai M, Wei J, Fujita M, Nakai M, Ho GJ, MasUah E, Akatsu H, Yamada T, Hashimoto M (2006) Increased level of DJ-1 in the cerebrospinal fluids of sporadic Parkinson s disease. Biochem Biophys Res Commun 345 967-972... 

Mandel S, Grunblatt E, Riederer P, Amariglio N, Jacob-Hirsch J, Rechavi G, Youdim MB (2005) Gene expression profiling of sporadic Parkinson s disease substantia nigra pars compacta reveals impairment of ubiquitin-proteasome subunits, SKPIA, aldehyde dehydrogenase, and chaperone HSC-70. Ann N Y Acad Sci 1053 356-375. 

The SCJDMM2 subtype has MM at PrP codon 129 and type 2 PrP , and it accounts for 2-8% of the sporadic cases. The mean age at onset is 65 years and the mean clinical duration is 16 months. Cognitive impairment is the universal presenting symptom and is sometimes accompanied by aphasia. At later stages, myoclonus and pyramidal signs, and sometimes Parkinsonism, apraxia, and seizures, develop. There is no PSW on EEG while CSF 14-3-3 is positive in most cases. 

PSP is the second most common cause of Parkinsonism typified by early gait instability and difficulty with vertical eye movement. PSP is characterized by neurofibrillary tangles composed almost entirely of sdaight filaments of four repeats of Tau protein. Although most cases of PSP appear to be sporadic, genetic diatheses have been implicated. De Yebenes described a pattern of inheritance consistent with a Mende-lian autosomal dominant disorder (De Yebenes et al., 1995). Difficulty recognizing the variable phenotypic expression of PSP may be one reason fewer familial cases have been identified than expected (Rojo et al., 1999). The HI haplotype of the Tau gene has also been found to have association with increased risk for PSP, as it has been for PD (Conrad et al.. 

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