Stephen R. Dlouhy

Phenotypic variability of Gerstmann-Straussler-Scheinker disease is associated with prion protein heterogeneity

Abstract. Gerstmann-StrSussler-Scheinker disease (GSS), a cerebello-pyramidal syndrome associated with dementia and caused by mutations in the priori protein gene (PRNP), is phenotypically heterogeneous. The molecular mechanisms responsible for such heterogeneity are unknown. Since we hypothesize that prion protein (PrP) heterogeneity may be associated with clinico-pathologic heterogeneity, the aim of this study was to analyze PrP in several GSS variants. Among the pathologic phenotypes of GSS, we recognize those without and with marked spongiform degeneration. In the latter (i.e. a subset of GSS P102L patients) we observed 3 major proteinase-K resistant PrP (PrPres) isoforms of ca. 21-30 kDa, similar to those seen in Creutzfeldt-Jakob disease. In contrast, the 21-30 kDa isoforms were not prominent in GSS variants without spongiform changes, including GSS A117V, GSS D202N, GSS Q212P, GSS Q217R, and 2 cases of GSS P102L. This suggests that spongiform changes in GSS are related to the presence of high levels of these distinct 21-30 kDa isoforms. Variable amounts of smaller, distinct PrPres isoforms of ca. 7-15 kDa were seen in all GSS variants. This suggests that GSS is characterized by the presence PrP isoforms that can be partially cleaved to low molecular weight PrPres peptides.

Prion Protein Amyloidosis

The prion protein (PrP) plays an essential role in the pathogenesis of a group of sporadic, genetically determined and infectious fatal degenerative diseases, referred to as “prion diseases”, affecting the central nervous system of humans and other mammals. The cellular PrP is encoded by a single copy gene, highly conserved across mammalian species. In prion diseases, PrP undergoes conformational changes involving a shift from α‐helix to β‐sheet structure. This conversion is important for PrP amyloidogenesis, which occurs to the highest degree in the genetically determined Gerstmann‐Sträussler‐Scheinker disease (GSS) and prion protein cerebral amyloid angiopathy (PrP‐CAA), while it is less frequently seen in other prion diseases. GSS and PrP‐CAA are associated with point mutations of the prion protein gene (PRNP); these conditions show a broad spectrum of clinical presentation, the main signs being ataxia, spastic paraparesis, extrapyramidal signs and dementia. In GSS, parenchyma! amyloid may be associated with spongiform changes or neurofibrillary lesions; in PrP‐CAA, vascular amyloid is associated with neurofibrillary lesions. A major component of the amyloid fibrils in the two diseases is a 7 kDa peptide, spanning residues 81–150 of PrP.

Gerstmann-Sträussler-Scheinker disease. II: Neurofibrillary tangles and plaques with PrP-amyloid coexist in an affected family

Azzarelli et al reported an Indiana kindred affected by a hereditary disorder, characterized clinically by ataxia, parkinsonism, and dementia. Recently, we studied neuropathologically the 3rd and 4th cases that came to autopsy among the patients of this family. As in 2 patients examined previously, amyloid plaques were widespread throughout the cerebrum and the cerebellum, whereas neurofibrillary tangles were numerous in the cerebral cortex, the hippocampus, and the substantia innominata. Amyloid plaques were not recognized by polyclonal antibodies against the Alzheimers disease amyloid A4 protein, but did contain epitopes recognized by antibodies against a prion protein. Spongiform changes were occasionally observed and were mild. Our findings indicate that this familial disorder is a form of or is related to Gerstmann-Sträussler-Scheinker disease. The consistent presence of numerous neurofibrillary tangles may be important in differentiating a distinct subgroup of patients with familial Gerstmann-Sträussler-Scheinker disease, and indicates that a disturbance of the cytoskeleton might be part of the neuronal pathology of Gerstmann-Sträussler-Scheinker disease.

Proteolipid protein is necessary in peripheral as well as central myelin

Alternative products of the proteolipid protein gene (PLP), proteolipid protein (PLP) and DM20, are major components of compact myelin in the central nervous system, but quantitatively minor constituents of Schwann cells. A family with a null allele of PLP has a less severe CNS phenotype than those with other types of PLP mutations. Moreover, individuals with PLP null mutations have a demyelinating peripheral neuropathy, not seen with other PLP mutations of humans or animals. Direct analysis of normal peripheral nerve demonstrates that PLP is localized to compact myelin. This and the clinical and pathologic observations of the PLP null phenotype indicate that PLP/DM20 is necessary for proper myelin function both in the central and peripheral nervous systems.

Amyloid fibrils in Gerstmann-Sträussler-Scheinker disease (Indiana and Swedish Kindreds) express only PrP peptides encoded by the mutant allele

Gerstmann-Sträussler-Scheinker (GSS) disease is a cerebral amyloidosis linked to mutations of the PRNP gene. We previously reported that the amyloid protein in the Indiana kindred of GSS is an internal fragment of prion protein (PrP). To investigate whether this fragment originates only from mutant or from both mutant and wild-type PrP, we have characterized amyloid proteins purified from patients of the Indiana and Swedish GSS families. These patients were heterozygous for the Met-Val polymorphism at PRNP codon 129 and carried a mutation at PRNP codon 198 (Phe-->Ser) and codon 217 (Gln-->Arg), respectively. The smallest amyloid subunit was a 7 kDa peptide spanning residues approximately 81 to approximately 150 in the Indiana patient and approximately 81 to approximately 146 in the Swedish patient. In both patients, only Val was present at position 129. Since Val-129 was in coupling phase with Ser-198 and Arg-217, our findings indicate that only the mutant PrP is involved in amyloid formation in both kindreds.

Genetics of Pelizaeus-Merzbacher Disease

Pelizaeus-Merzbacher disease (PMD) has been recognized as a clinical entity for more than a century. It has gradually become apparent that the disorder is a dysmyelination, in distinction to demyelinating conditions such as adrenoleukodystrophy. The failure to deposit myelin is due to decreased production of its chief protein, proteolipid protein (PLP). In about 30% of patients with the diagnosis of PMD there is a mutation in the coding portion of the proteolipid protein gene, PLP. This gene is located at Xq22 so the disease in these families shows an X-linked pattern of inheritance. The expression of the mutant gene is generally recessive, but some mutations are expressed frequently in females. At least some patients with PMD that do not show mutations in the coding region of PLP demonstrate linkage between the disease and PLP. As additional mutations in PLP are discovered, it is becoming apparent that the nosology of PLP-associated disease is changing. PMD now comprises a spectrum of disorders with similar but not necessarily identical clinical pictures. Some of these disorders may be certain forms of X-linked paraplegia, SPG2. Finally, some diseases that look like PMD may not be X-linked.

Gerstmann-Sträussler-Scheinker Disease and the Indiana Kindred

Gerstmann‐Sträussler‐Scheinker disease is an autosomal dominant disorder with a wide spectrum of clinical presentations including ataxia, spastic paraparesis, extrapyramidal signs, and dementia. The patients present with symptoms in the third to sixth decade of life and the mean duration of illness is five years. Mutations at codons 102, 105, 117, 145, 198 and 217 of the open reading frame of the prion protein gene have been associated with GSS disease. As a result of the mutations, a substitution at the corresponding residues of the prion protein occurs, or as in the case of the STOP mutation at codon 145, a truncated protein is produced. Neuropathologically, the common denominator is a cerebral prion protein amyloidosis; however, there is significant variability in the pattern of amyloid deposition in regions of the central nervous system among reported families. Amyloidosis coexists with severe spongiform degeneration in patients with the mutation at codon 102, and with neurofibrillary degeneration in the patients with mutation at codons 145, 198 and 217. The development of a transmissible spongiform encephalopathy in animals inoculated with brain tissue from affected subjects with mutation at codon 102 suggests that in some formsofgenetically‐determined Gerstmann‐Sträussler‐Scheinker disease, and particularly those characterized by severe spongiosis, amyloidogenesis and production of an infectious “agent” occur concomitantly via mechanisms that are only partially understood.

The Relationship Between CAG Repeat Length and Age of Onset Differs for Huntington's Disease Patients with Juvenile Onset or Adult Onset

Age of onset for Huntingtons disease (HD) varies inversely with the length of the disease‐causing CAG repeat expansion in the HD gene. A simple exponential regression model yielded adjusted R‐squared values of 0.728 in a large set of Venezuelan kindreds and 0.642 in a North American, European, and Australian sample (the HD MAPS cohort). We present evidence that a two‐segment exponential regression curve provides a significantly better fit than the simple exponential regression. A plot of natural log‐transformed age of onset against CAG repeat length reveals this segmental relationship. This two‐segment exponential regression on age of onset data increases the adjusted R‐squared values by 0.012 in the Venezuelan kindreds and by 0.035 in the HD MAPS cohort. Although the amount of additional variance explained by the segmental regression approach is modest, the two slopes of the two‐segment regression are significantly different from each other in both the Venezuelan kindreds [F(2, 439) = 11.13, P= 2 × 10−5] and in the HD MAPS cohort [F(2, 688) = 38.27, P= 2 × 10−16]. In both populations, the influence of each CAG repeat on age of onset appears to be stronger in the adult‐onset range of CAG repeats than in the juvenile‐onset range.

Prion proteins with different conformations accumulate in Gerstmann-Sträussler-Scheinker disease caused by A117V and F198S mutations

Gerstmann-Sträussler-Scheinker disease (GSS) is characterized by the accumulation of proteinase K (PK)-resistant prion protein fragments (PrP(sc)) of approximately 7 to 15 kd in the brain. Purified GSS amyloid is composed primarily of approximately 7-kd PrP peptides, whose N terminus corresponds to residues W(81) and G(88) to G(90) in patients with the A117V mutation and to residue W(81) in patients with the F198S mutation. The aim of this study was to characterize PrP in brain extracts, microsomal preparations, and purified fractions from A117V patients and to determine the N terminus of PrP(sc) species in both GSS A117V and F198S. In all GSS A117V patients, the approximately 7-kd PrP(sc) fragment isolated from nondigested and PK-digested samples had the major N terminus at residue G(88) and G(90), respectively. Conversely, in all patients with GSS F198S, an approximately 8-kd PrP(sc) fragment was isolated having the major N terminus start at residue G(74). It is possible that a further degradation of this fragment generates the amyloid subunit starting at W(81). The finding that patients with GSS A117V and F198S accumulate PrP(sc) fragments of different size and N-terminal sequence, suggests that these mutations generate two distinct PrP conformers.

Gerstmann‐Sträussler‐Scheinker disease. I. Extending the clinical spectrum

We present the clinical findings in affected members of a large kindred with Gerstmann-Sträussler-Scheinker disease. Sixty-four patients exhibited progressive ataxia, dementia, and parkinsonian features. Inheritance appears to be autosomal dominant. Impaired smooth-pursuit eye movements, defective short-term memory, clumsiness of the hands, and ataxia of gait develop in the late 30s to early 60s. Eye movement abnormalities are characteristic of cerebellar dysfunction. Dementia progresses gradually over several years. Later, rigidity and bradykinesia appear and, at this stage, there is often psychosis or severe depression with rapid weight loss. Death occurs in 6 months to 2 years after onset of rigidity. Magnetic resonance imaging in 2 affected individuals showed cerebellar atrophy. There is decreased T2 signal in the basal ganglia, consistent with iron deposition.