Prion

The prion protein M129V polymorphism

To cite this article: Ewa Golanska, Monika Sieruta, Elizabeth Corder, Sylwia M. Gresner, Anna Pfeffer, Malgorzata Chodakowska-Zebrowska, Tomasz M. Sobow, Izabela Klich, Malgorzata Mossakowska, Aleksandra Szybinska, Maria Barcikowska & Pawel P. Liberski (2013) The prion protein M129V polymorphism, Prion, 7:3, 244-247, DOI: 10.4161/pri.23903

To link to this article: http://dx.doi.org/10.4161/pri.23903

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The prion protein M129V Longevity and cognitive impairment among Polish centenarians

Ewa Golanska,1,†,* Monika Sieruta,1,† Elizabeth Corder,2 Sylwia M. Gresner,1 anna Pfeffer,3 Malgorzata Chodakowska-Zebrowska,4 tomasz M. Sobow,5 izabela Klich,6 Malgorzata Mossakowska,7 aleksandra Szybinska,7 Maria Barcikowska3 and Pawel P. Liberski1

1Department of Molecular Pathology and neuropathology; Medical university of Lodz; Lodz, Poland; 2Matrix Genomics, inc.; Santa Fe, nM uSa; 3Department of neurodegenerative Disorders; Mossakowski Medical research Centre; Polish academy of Sciences; Warsaw, Poland; 4neurology Clinic; Central Clinical hospital CSK MSWia; Warsaw, Poland; 5Department of Medical Psychology; Medical university of Lodz; Lodz, Poland; 6Department of Paediatrics, oncology, haematology and Diabetology; Medical university of Lodz; Lodz, Poland; 7Laboratory of neurodegeneration; international institute of Molecular and Cell Biology; Warsaw, Poland

†these authors contributed equally to this work.

the PRNP gene encodes the cellular isoform of prion protein (PrPC). the M129V polymorphism influences the risk of prion diseases and may modulate the rate of neurodegeneration with age. We present the first study of the polymorphism among Polish centenarians. in the control group (n = 165, ages 18 to 56 years) the observed M129V genotype frequencies agreed with those expected according to the hardy-Weinberg equilibrium (MM, MV and VV): 43, 44 and 13% (hWE p > 0.05). among centenarians (n = 150, ages 100 to 107) both homozygotes were more common than expected and hWE was rejected: 46, 37 and 17% (expected 42, 46 and 13%; hWE p = 0.025). this finding is consistent with a higher mortality rate among heterozygotes. however, the observed allele and genotype frequencies did not differ significantly between the oldest-old and the young controls. the genotypic frequencies were not related to severe cognitive impairment

associated with greater brain amyloid deposition.6,7 The codon 129 polymorphism was proposed as a risk factor for Alzheimer disease (AD) (MM conferring elevated risk), mild temporal lobe epilepsy and primary progressive aphasia.8-11 Its influence on sur- vival in AD, clinical presentation of idiopathic Parkinson dis- ease and clinical course of neurological Wilson disease has also been reported.12-14 This raises the possibility of selective mor- tality depending on codon 129 genotype. Moreover, in healthy individuals a link between the M129V polymorphism and long- term memory and cognitive performance has been described.15,16 However, not all studies find associations.17-20

The PRNP gene encodes the cellular isoform of the prion protein (PrPC: normal conformation; PrPSc: misfolded). There is ample reason to consider inherited variation in the protein as relevant to prion disease: Experimental data implicate PrPC in anti-apoptotic activities, cell signaling and adhesion, synaptic function and protection against oxidative stress (for a review, see ref. 1), although exact physiological mechanisms for normal and altered forms remain elusive. Clearly, misfolding to PrPSc plays a central causal role in the pathogenesis of Creutzfeldt-Jakob disease (CJD) and other spongiform encephalopathies.2 Rare inherited mutations in PRNP cause familial forms of prion diseases. The common M129V methionine to valine polymorphism at codon 129 influences the risks of sporadic and acquired iatrogenic CJD: the homozygous MM and VV genotypes are both over- represented as compared to the heterozygous MV genotype.3,4 All pathologically confirmed cases of variant CJD reported to date are homozygous MM.5

These reported studies concern middle-aged individuals or persons at most in their 80s or 90s, not the oldest-old, who have selectively survived, avoided, fatal condi- In this paper we present the first genetic association study the PRNP codon 129 polymorphism among Polish centenar- (n = 150) comparing genotypic frequencies to those found a sample of younger Poles aged 18 to 56 years (n = 165). the centenarians, genotype frequencies are contrasted subjects with (n = 82) and without severe cognitive impair- (n = 33).