IVIG Delays Onset in a Mouse Model of Gerstmann-Sträussler-Scheinker Disease

Gu, Huiying; Kirchhein, Yvonne; Zhu, Timothy; Zhao, Gang; Peng, Hongjun; Du, Eileen; Liu, Junyi; Mastrianni, James A.; Farlow, Martin R.; Dodel, Richard; Du, Yansheng

doi:10.1007/s12035-018-1228-0

Cited by 5 publications

(4 citation statements)

References 40 publications

(45 reference statements)

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“… 31 32 33 Studies focusing on genetic prions are rare. Gu et al 34 reported that intravenous immunoglobulin inhibited the formation of PrP amyloid plaques, suggesting onset delay effects in a transgenic A116V GSS model mouse. Problems associated with exploring therapies for prion diseases, particularly the PRNP P102L variant, include their clinical heterogeneity and extremely low prevalence.…”

Section: Discussionmentioning

confidence: 99%

Accumulation Area of a Japanese PRNP P102L Variant Associated With Gerstmann-Sträussler-Scheinker Disease: The Ariake PRNP P102L Variant

Suzuyama,

Eriguchi,

Minagawa

et al. 2024

J Clin Neurol

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Background and Purpose The coast of Kyushu Island on Ariake Sea in Japan is known to be an accumulation area for patients with a proline-to-leucine substitution mutation at residue 102 (P102L) of the human prion protein gene ( PRNP ), which is associated with Gerstmann–Sträussler–Scheinker disease. We designated this geographical distribution as the “Ariake PRNP P102L variant.” The purpose of this study was to characterize the clinical features of this variant. Methods We enrolled patients with the PRNP P102L variant who were followed up at the Saga University Hospital from April 2002 to November 2019. The clinical information of patients were obtained from medical records, including clinical histories, brain magnetic resonance imaging (MRI), and electroencephalography (EEG). A brain autopsy was performed on one of the participants. Results We enrolled 24 patients from 19 family lines, including 12 males. The mean age at symptom onset was 60.6 years (range, 41–77 years). The incidence rate of the Ariake PRNP P102L variant was 3.32/1,000,000 people per year in Saga city. The initial symptoms were ataxia (ataxic gait or dysarthria) in 19 patients (79.2%), cognitive impairment in 3 (12.5%), and leg paresthesia in 2 (8.3%). The median survival time from symptom onset among the 18 fatal cases was 63 months (range, 23–105 months). Brain MRI revealed no localized cerebellar atrophy, but sparse diffusion-weighted imaging abnormalities were detected in 16.7% of the patients. No periodic sharp-wave complexes were identified in EEG. Neuropathological investigations revealed uni- and multicentric prion protein (PrP) plaques in the cerebral cortex, putamen, thalamus, and cerebellum of one patient. Western blot analysis revealed 8-kDa proteinase-K-resistant PrP. Conclusions This is the first report of the accumulation area of a PRNP P102L variant on the coast of Ariake Sea. The Ariake PRNP P102L variant can be characterized by a relatively long disease duration with sparse abnormalities in brain MRI and EEG relative to previous reports. Detailed interviews to obtain information on the birthplace and the family history of related symptoms are important to diagnosing a PRNP P102L variant.

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Section: Discussionmentioning

confidence: 99%

Accumulation Area of a Japanese PRNP P102L Variant Associated With Gerstmann-Sträussler-Scheinker Disease: The Ariake PRNP P102L Variant

Suzuyama,

Eriguchi,

Minagawa

et al. 2024

J Clin Neurol

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“…It has been previously shown that non-specific clearance therapies (rapamycin and IVIG) but not Anle138b can delay the onset of disease in a transgenic mouse model of Gerstmann-Sträussler-Scheinker (GSS) syndrome (36)(37)(38). Our current study differs from these prior studies because (1) GSS is a phenotypically distinct inherited prion disease characterized by the accumulation of amyloid plaques not seen in FFI or fCJD, and ( 2) we used knock-in rather than overexpression animal models.…”

Section: Discussionmentioning

confidence: 99%

Anti-prion drugs do not improve survival in knock-in models of inherited prion disease

Walsh,

Rees,

Mehra

et al. 2023

Preprint

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Prion diseases uniquely manifest in three distinct forms: inherited, sporadic, and infectious. Wild-type prions are responsible for the sporadic and infectious versions, while mutant prions cause inherited variants like fatal familial insomnia (FFI) and familial Creutzfeldt-Jakob disease (fCJD). Although some drugs can prolong prion incubation times up to four-fold in rodent models of infectious prion diseases, no effective treatments for FFI and fCJD have been found.In this study, we evaluated the efficacy of various anti-prion drugs on newly-developed knock-in mouse models for FFI and fCJD. These models express bank vole prion protein (PrP) with the pathogenic D178N and E200K mutations. We applied various drug regimens known to be highly effective against wild-type prionsin vivoas well as a brain-penetrant compound that inhibits mutant PrPScpropagationin vitro. None of the regimens tested (Anle138b, IND24, Anle138b + IND24, cellulose ether, and PSCMA) significantly extended disease-free survival or prevented mutant PrPScaccumulation in either knock-in mouse model, despite their ability to induce strain adaptation of mutant prions. Paradoxically, the combination of Anle138b and IND24 appeared to accelerate disease by 16% and 26% in kiBVIE200Kand kiBVID178Nmice, respectively, and accelerated the aggregation of mutant PrP moleculesin vitro. Our results show that anti-prion drugs originally developed to treat infectious prion diseases do not necessarily work for inherited prion diseases, and that the recombinant sPMCA is not a reliable platform for identifying compounds that target mutant prions. This work underscores the need to develop therapies and validate screening assays specifically for mutant prions.

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“…[ 4 ] A study on a transgenic mouse model for GSS indicated that intravenous immunoglobulin may be a potential effective therapeutic treatment for GSS. [ 19 ] GSS usually has a poor prognosis. The disease progression extends over a period of 3.5 to 9.5 years [ 20 ] and the mean disease duration is close to 5 years.…”

Section: Discussionmentioning

confidence: 99%

Gerstmann-Sträussler-Scheinker syndrome misdiagnosed as cervical spondylotic myelopathy

Feng

Huang

et al. 2021

Medicine

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Rationale: Gerstmann-Sträussler-Scheinker syndrome (GSS) is a rare autosomal dominant disease caused by a mutation in the prion protein gene ( PRNP ) that is not well known among neurologists and is therefore easily misdiagnosed. Patient concerns : A 49-year-old man was admitted for the first time because of an unsteady walk with mogilalia for 1 year. He underwent a cervical discectomy and a plate-screw fixation 6 months prior, although postoperative gait instability did not improve. Diagnosis: Whole exome sequencing identified a pathogenic and heterozygous mutation in the PRNP 4 years after onset. The patient was eventually diagnosed with GSS. Interventions: Symptomatic treatment to improve cerebrocirculation and cerebrometabolism was provided. Outcomes: The neurological decline continued. The Mini-Mental State Examination and modified Rankin Scale scores changed from 19 to 11 and 2 to 5, respectively. Progressive cerebral and cerebellar atrophy on magnetic resonance imaging was observed. Lessons: Cerebral and cerebellar atrophy are neuroimaging features symptomatic of GSS that become more apparent as the disease progresses. This atrophy is positively correlated with the severity of symptoms and reduced quality of life. Neurologists treating middle-aged patients with progressive ataxia, cognitive impairment or dysarthria, and brain atrophy need to consider the possibility of GSS.

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IVIG Delays Onset in a Mouse Model of Gerstmann-Sträussler-Scheinker Disease

Cited by 5 publications

References 40 publications

Accumulation Area of a Japanese PRNP P102L Variant Associated With Gerstmann-Sträussler-Scheinker Disease: The Ariake PRNP P102L Variant

Accumulation Area of a Japanese PRNP P102L Variant Associated With Gerstmann-Sträussler-Scheinker Disease: The Ariake PRNP P102L Variant

Anti-prion drugs do not improve survival in knock-in models of inherited prion disease

Gerstmann-Sträussler-Scheinker syndrome misdiagnosed as cervical spondylotic myelopathy

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