Prion protein gene in Alzheimer's disease

O gene da proteína priônica na doença de Alzheimer

Alzheimer's disease (AD) is a complex disorder, including sporadic (representing the majority of cases) and familial forms, the latter being usually linked to a genetic etiology. Three major genes have been already described as the cause of AD: amyloid precursor protein (APP) gene, presenilin 1 gene (PSEN1), and presenilin 2 gene (PSEN2), typically presenting with an early onset (before 60 years). However, these genetic forms are responsible for less than 5% of all AD cases¹. Conversely, more common gene polymorphisms, such as the presence of the ϵ4 allele of the apolipoprotein E (APOE) gene, are associated with an increased risk of developing late-onset AD²,³. Numerous other candidate genes have been identified, especially through genome-wide association studies, and are currently the topic of intensive research¹,².

Among the polymorphisms that have been explored in relation to AD, homozygosis for methionine at codon 129 of the prion protein gene (PRNP) has been associated with a 1.3-fold increased risk of developing the disease in populations of Caucasian origin, in comparison with heterozygosis (i.e., methionine/valine), according to a meta-analysis⁴. However, these findings have not been confirmed by other investigators, particularly in a study including patients with definite AD⁵.

Human prion diseases, although very rare, share some neuropathological features with AD, especially the accumulation of misfolded proteins [prion protein (PrP^C) and β-amyloid] in the brain tissue. Moreover, PrP^C seems to function as a receptor for the β-amyloid oligomers, and this interaction could mediate the characteristic neurotoxicity of AD pathology, leading to synaptic failure and cognitive decline⁶,⁷.

Within this context, the paper published in this issue of Arquivos de Neuro-Psiquiatria by Smid et al.⁸ adds another piece of information to this intriguing and interesting puzzle. The authors conducted a case-control study comparing PRNP polymorphisms in AD patients and matched controls, and they also explored associations between the genotypes and cognitive performance. No genotype differences were found between AD and controls in relation to PRNP, even when APOE genotype was taken into account in the analysis. Moreover, cognitive performance was not influenced by PRNP polymorphisms.

Hence, the overall results of the study are essentially negative. This could be explained by sample size limitations or by the ethnic background of the population, possibilities that were already acknowledged by the authors. On the other hand, the findings are in agreement with those of previous reports, particularly with the sole neuropathological investigation published on this topic⁵. No similar data from other Brazilian populations are available for comparison, as this is the first study to have explored PRNP polymorphisms in AD in the country. This latter feature brings special relevance to the present study. We need more and better information about the genetics of dementia in Brazil and in other developing countries, either to confirm or to refute current candidate genes, as well as to identify new ones, which may ultimately contribute to improve our understanding about the pathogenesis of these devastating conditions.

References

• ¹
  Tanzi RE. The genetics of Alzheimer disease. Cold Spring Harb Perspect Med 2012;2:6296.
• ²
  Bettens K, Sleegers K, Van Broeckhoven C. Genetic insights in Alzheimer's disease. Lancet Neurol 2013;12:92-104.
• ³
  Bahia VS, Kok F, Marie SN, Shinjo SO, Caramelli P, Nitrini R. Polymorphisms of APOE and LRP genes in Brazilian individuals with Alzheimer disease. Alzheimer Dis Assoc Disord 2008;22:61-65.
• ⁴
  Del Bo R, Scarlato M, Ghezzi S, et al. Is M129V of PRNP gene associated with Alzheimer disease? A case-control study and meta-analysis. Neurobiol Aging 2008;27:770-775.
• ⁵
  Poleggi A, Bizzarro A, Acciarri A, et al. Codon 129 polymorphism of prion protein gene in sporadic Alzheimer's disease. Eur J Neurol 2008;15:173-178.
• ⁶
  Caetano FA, Beraldo FH, Hajj GN, et al. Amyloid-beta oligomers increase the localization of prion protein at the cell surface. J Neurochem 2011;117:538-553.
• ⁷
  Ferreira ST, Klein WL. The Aβ oligomer hypothesis for synapse failure and memory loss in Alzheimer's disease. Neurobiol Learn Mem 2011;96:529-543.
• ⁸
  Smid J, Landemberger MC, Bahia VS, Martins VR, Nitrini R. Codon 129 polymorphism of prion protein gene in Alzheimer's disease in a Brazilian population. Arq Neuropsiquiatr 2013;71:423-427.

Publication Dates

• Publication in this collection
  July 2013

History

• Received
  14 May 2013
• Accepted
  21 May 2013