By J. Cole. Tulane University.
However generic cytotec 100 mcg line, they are dependent on the import of proteins to function purchase 100 mcg cytotec. NUCLEUS affecting either the synthesis of The largest of the subcellular organelles of animal cells is the nucleus (Fig generic cytotec 200mcg overnight delivery. For example cytotec 200 mcg otc, nucleus, which are composed of DNA, an equal weight of small, positively charged adrenoleukodystrophy probably involves a proteins called histones, and a variable amount of other proteins. This nucleoprotein mutation that decreases the content of a transporter in the peroxisomal membrane. Zellweger’s syndrome is caused by the failure to complete the synthesis of peroxisomes. Nucleolus Pores Nuclear envelope Euchromatin Heterochromatin 3–10 µm Nucleolus Pores Nuclear envelope Chromatin Outer (DNA + histones membrane and other proteins) (continuous with RER) Fig. Electron micrograph (top); three-dimensional drawing (bottom). CHAPTER 10 / RELATIONSHIP BETWEEN CELL BIOLOGY AND BIOCHEMISTRY 173 complex is called chromatin. The nucleolus, a substructure of the nucleus, is the site of rRNA transcription and processing, and of ribosome assembly. Replication, tran- scription, translation, and the regulation of these processes are the major focus of the molecular biology section of this text (see Section Three). The nucleus is separated from the rest of the cell (the cytoplasm) by the nuclear envelope, which consists of two membranes joined at nuclear pores. The outer nuclear membrane is continuous with the rough endoplasmic reticulum. To convert the genetic code of the DNA into the primary sequence of a protein, DNA is tran- scribed into RNA, which is modified and edited into mRNA. The mRNA travels through the nuclear pores into the cytoplasm, where it is translated into the primary sequence of a protein on ribosomes (Fig. Ribosomes, which are generated in the nucleolus, also must travel through nuclear pores to the cytoplasm. Conversely, proteins required for replication, transcription, and other processes pass into the nucleus through these pores. Thus, transport through the pore is specific for the molecule and the direction of transport. Specificity and direction of travel through the nuclear pore (import vs. Proteins transported into the nucleus have a nuclear localization signal that causes them to bind to one of the subunits of cytosolic proteins called importins. The other subunit of the importin molecule binds to cytoplasmic filaments attached to the outer ring of the nuclear pore. As the importin-protein complex enters the nucleus, the small GTP-binding protein Ran binds to an importin subunit, causing release of the transported protein into the nucleus. The Ran-importin complex is returned to the cytosol, where Ran- GAP (GTPase activating protein) activates hydrolysis of bound GTP to GDP and phosphate. The energy released by GTP hydrolysis changes the conformation of Ran and the complex dissociates. Ras and Ran belong to a superfamily of proteins called small G proteins (also called small GTP- Table 10. These proteins function as tim- Ras Regulator of gene H-Ras, K-Ras, N-Ras, Anchored to plasma ing regulators for a variety of cell functions. When small G proteins contain actin cytoskeleton and Rac (1-3) membrane by lipids, and bound GTP, they bind to and activate their gene expression (F-actin translocates to cytosol target proteins. As their bound GTP is bundling, myosin filament assembly) hydrolyzed to GDP and Pi, their conforma- Arf/Sar Assembly of coatomer- Arf (1-6), Sar 1a,1b; Arf is anchored to tion changes dramatically, and they dissoci- coated vesicles (COPI Arl (1-7) vesicular membranes by ate from the target protein. They thus serve and COPII) for vesicular myristyl groups, but Sar is as “automatic clocks” that shut themselves trafficking pathways anchored by the protein originating in the Golgi itself. Many of the monomeric GTP binding Rab Targeting of vesicles Dynamin, Rab Anchored to lipid proteins are regulated by GAPs (GTPase involved in secretory (11-33) membranes with activating proteins), GEFs (GTP exchange and endocytotic geranylgeranyl (C20 proteins which stimulate GDP dissociation pathways and formation isoprenoid) groups and and GTP binding), or GDIs (GDP-dissociation of v-SNARE–t-SNARE other lipids complexes inhibitory proteins).
Even patients who reported a negative family history of PD actually had a prevalence rate of PD in relatives more than three times higher than that in the general population purchase 200 mcg cytotec otc. A study of the Icelandic population (13) revealed the presence of genetic as well as environmental components in the etiology of late-onset PD (onset at >50 years of age) purchase 100 mcg cytotec fast delivery. The most recent epidemiological study cytotec 200mcg free shipping, conducted by Maher and colleagues (14) on 203 sibling pairs with PD order cytotec 100mcg overnight delivery, also supported a genetic contribution to the etiology of PD. This study showed that sibling pairs with PD were more similar in age at symptomatic disease onset than in year of symptomatic disease onset. TWIN STUDIES Studies of twins can provide a powerful conﬁrmation of the genetic contribution to the etiology of a neurodegenerative condition. If a genetic component is present, concordance will be greater in monozygotic (MZ) than in dizygotic (DZ) twins. If a disorder is exclusively genetic in origin and the diagnosis is not compounded by age-associated penetrance or stochastic or environmental factors, MZ concordance may be close to 100%. Although earlier twin studies in PD were inconclusive (15–17), the most recent twin study, conducted by Tanner and colleagues (18) on a large cohort of twins, demonstrated the presence of genetic factors in the etiology of PD if disease begins at or before age 50 years. This was a study of twins enrolled in the National Academy of Science/National Research Council World War II Veteran Twin Registry. No genetic component was evident when the onset of symptoms occurred after age 50 years. However, twin studies such as this one, which was based exclusively on clinical observations, may require extended longitudinal follow-up to conﬁrm the presence of PD in a co-twin (19). Indeed, reduced striatal uptake of 6FD has been demonstrated in some clinically asymptomatic co-twins (20). Using longitudinal evaluation with measure- ment of 6FD, Piccini and colleagues (21) demonstrated 75% concordance of PD in MZ twins versus 22% in DZ twins. EVALUATION OF KINDREDS Kindreds with a parkinsonian phenotype have been reported in the world literature since the nineteenth century (22,23). In a review of literature in 1926, Bell and Clark (24) described 10 families with ‘‘shaking palsy’’ believed to exist on a hereditary basis. They also provided 20 references of earlier accounts of familial paralysis agitans. In 1937, Allen (25) detailed an additional 25 families with inherited parkinsonism and speculated that in approximately two thirds of these kindreds the inheritance was autosomal dominant and probably the result of a ‘‘single autosomal gene. In the levodopa era, a number of reports described families with PD and PPS (22), including two very large multigenerational kindreds known as Contursi and Family C (German-American) (27,28). With progress in molecular genetic techniques, the importance of collecting data from parkinsonian families with PD and PPS phenotypes has grown exponentially. Table 1 summarizes the status of current knowledge of the genetics of PD and related conditions. It shows the types of inheritance and the location of known chromosomal loci and mutations. ASSOCIATION STUDIES Despite substantial progress in identiﬁcation, the number of known large pedigrees with PD or PPS is still small. Furthermore, genetic linkage studies, which use ‘‘identity-by-descent’’ mapping, have been hampered because the amount of DNA available from affected pedigree members is limited, generally as a result of death, lack of consent, or geographic dispersion. Association or ‘‘identity-by-state’’ mapping is an alternate approach employing groups of unrelated individuals. Association studies measure differences in genetic variability between a group with the disease in question and a group of matched, normal individuals. This method is most powerful in implicating genes for multigenic traits in homogeneous population isolates. However, many past studies have been confounded by misconceived, a priori notions of disease etiology and by clinical, locus, and allelic heterogeneity. Studies must be reproducible, preferably in different ethnic populations, and the genetic variability should have some functional consequence (either directly or in disequilibrium) that alters gene expression or the resultant protein. The genes for a-synuclein, ubiquitin C-terminal hydrolase, parkin, and tau harbor mutations that segregate with parkinsonism in large multiply affected kindreds (31,33,34,37,43) (Fig. Although the relevance of these ﬁndings for sporadic PD is unclear, there is no doubt that these genes mark a pathway that is perturbed in both familial and sporadic PD.
Parkinson Variants in the General Population As noted above proven cytotec 200mcg, this classiﬁcation in epidemiological surveys can only be approximate as the ﬁnal diagnosis may not be possible until after autopsy (7) cheap cytotec 100 mcg on-line. PS classiﬁcation has been evolving with time even within the same community (28 generic cytotec 200mcg with mastercard,29 generic cytotec 200mcg overnight delivery,34,35). Following the ﬁrst description in 1817 by James Parkinson (43) and the discovery of substantia nigra neuronal loss and LB inclusions, parkinsonism was regarded as a single clinicopathological entity. After von Economo encephalitis, an estimated 60% of the victims developed PS, which was classiﬁed as postencephalitic parkinsonism (PEP) (44,45). At one time, these patients constituted a large proportion of the PS cases in the general population. No new PEP cases have been reported since the mid-1950s (Table 1). Arteriosclerosis was once reported as a common cause of PS (34,35), but that is a very rare diagnosis now (28,29). This apparent reduction in arteriosclerosis as a cause of PS is due to increased diagnostic accuracy of PS, rather than a dramatic decline in arteriosclerosis in the general population. Neuroleptic-induced parkinsonism (DIP) was ﬁrst recognized in the late 1950s and is now a common PS variant (28,29,38) accounting for between 7% (28) and 20% of all PS cases (29). DIP is now the second most common PS variant and is more common in women than men (29). Large clinicopathological studies of Shy-Drager syndrome (SDS) (46), striatonigral degeneration (SND) (47), and progressive supranuclear palsy (PSP) (48) were ﬁrst reported in the 1960s, though clinical description of PSP was documented in the nineteenth century (49). Olivopontocerebellar atrophy (OPCA), which often includes some features of PS, has been known since 1900. The current classiﬁcation includes SND, SDS, and OPCA under the common heading of multiple system atrophy (MSA). Prominent dysautonomia in SDS and akinetic rigid PS features in SND were not fully recognized until 1960 and 1964, respectively, and in all likelihood such cases prior to that were classiﬁed as PEP or atypical parkinsonism because they occurred at a relatively young age and had widespread nervous system involvement. In spite of the improved understanding of these uncommon PS variants, the diagnosis is not always possible clinically (7,21,22,50). Autopsy series may be biased because the families of those suffering from the unusual Copyright 2003 by Marcel Dekker, Inc. PS variants may have heightened interest in ﬁnding out the nature of the disease and, therefore, be more likely to consent to an autopsy. The true frequency of these variants in the general population is, therefore, not possible to determine. A previous study from the same community reported PSP diagnosis in 1. Thus, MSA and PSP each represent less than 5% of the contemporary PS cases in North America. The most common PS variant in epidemiological studies (28,38,51) is idiopathic PD (6). The proportion of those with PD, however, varies widely in different studies—e. Preponderance of PD is also noted in autopsy studies of unselected PS cases (27,52,53). Dementia with Lewy bodies (DLB) is now a well-recognized entity (54), and extrapyramidal features may also be seen in Alzheimer’s disease (AD) (55). One recent PS study (29) noted that 14% of all PS cases had dementia manifesting within one year of PS onset and classiﬁed these as ‘‘Parkinson- ism in dementia. The clinical and pathological classiﬁcation of PS variants continues to evolve, but the most common variant is still PD (6,7). Life Expectancy in Parkinsonism All the PS variants limit mobility.